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{{Short description|Mammalian protein found in Homo sapiens}}
{{Short description|Mammalian protein found in Homo sapiens}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox gene}}
{{Infobox gene}}
'''Cyclin-dependent kinase 1''' also known as '''CDK1''' or '''cell division cycle protein 2 homolog''' is a highly conserved [[protein]] that functions as a serine/threonine [[kinase]], and is a key player in [[cell cycle]] regulation.<ref name="isbn0-19-920610-4">{{cite book | author = Morgan, David L. | title = The cell cycle: principles of control | publisher = New Science Press | location = London | year = 2007 | pages = 30–31 | isbn = 978-0-19-920610-0 }}</ref> It has been highly studied in the budding yeast ''[[Saccharomyces cerevisiae|S. cerevisiae]]'', and the fission yeast ''[[Schizosaccharomyces pombe|S. pombe]]'', where it is encoded by [[gene]]s ''cdc28'' and [https://www.pombase.org/gene/SPBC11B10.09 ''cdc2''], respectively.<ref name="pmid8507488">{{cite journal | vauthors = Nasmyth K | title = Control of the yeast cell cycle by the Cdc28 protein kinase | journal = Curr. Opin. Cell Biol. | volume = 5 | issue = 2 | pages = 166–179 | date = April 1993 | pmid = 8507488 | doi = 10.1016/0955-0674(93)90099-C }}</ref> In humans, Cdk1 is encoded by the ''CDC2'' gene.<ref name="pmid3553962">{{cite journal | last1=Lee|first1=Melanie|author-link1=Melanie Lee|last2=Nurse|first2=Paul|author-link2=Paul Nurse | title = Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2 | journal = Nature | volume = 327 | issue = 6117 | pages = 31–35 | date = Jun 1987 | pmid = 3553962 | doi = 10.1038/327031a0 |bibcode=1987Natur.327...31L|s2cid=4300190}}</ref> With its [[cyclin]] partners, Cdk1 forms complexes that [[phosphorylation|phosphorylate]] a variety of target substrates (over 75 have been identified in budding yeast); phosphorylation of these proteins leads to cell cycle progression.<ref name="pmid20465793">{{cite journal | vauthors = Enserink JM, Kolodner RD | title = An overview of Cdk1-controlled targets and processes | journal = Cell Division | volume = 5 | issue = 11 | pages = 11 | date = May 2010 | pmid = 20465793 | pmc = 2876151 | doi = 10.1186/1747-1028-5-11 }}</ref>
'''Cyclin-dependent kinase 1''' also known as '''CDK1''' or '''cell division cycle protein 2 homolog''' is a highly conserved [[protein]] that functions as a [[serine/threonine protein kinase]], and is a key player in [[cell cycle]] regulation.<ref name="isbn0-19-920610-4">{{cite book | author = Morgan, David L. | title = The cell cycle: principles of control | publisher = New Science Press | location = London | year = 2007 | pages = 30–31 | isbn = 978-0-19-920610-0 }}</ref> It has been highly studied in the budding yeast ''[[Saccharomyces cerevisiae|S. cerevisiae]]'', and the fission yeast ''[[Schizosaccharomyces pombe|S. pombe]]'', where it is encoded by [[gene]]s ''cdc28'' and [https://www.pombase.org/gene/SPBC11B10.09 ''cdc2''], respectively.<ref name="pmid8507488">{{cite journal | vauthors = Nasmyth K | title = Control of the yeast cell cycle by the Cdc28 protein kinase | journal = Current Opinion in Cell Biology | volume = 5 | issue = 2 | pages = 166–179 | date = April 1993 | pmid = 8507488 | doi = 10.1016/0955-0674(93)90099-C }}</ref> With its [[cyclin]] partners, Cdk1 forms complexes that [[phosphorylation|phosphorylate]] a variety of target substrates (over 75 have been identified in budding yeast); phosphorylation of these proteins leads to cell cycle progression.<ref name="pmid20465793">{{cite journal | vauthors = Enserink JM, Kolodner RD | title = An overview of Cdk1-controlled targets and processes | journal = Cell Division | volume = 5 | issue = 11 | pages = 11 | date = May 2010 | pmid = 20465793 | pmc = 2876151 | doi = 10.1186/1747-1028-5-11 | doi-access = free }}</ref>


== Structure ==
== Structure ==
[[Image:PBB Protein CDK2 image.jpg|thumb|left|'''Crystal Structure of the human Cdk1 homolog, Cdk2''']]
[[Image:PBB Protein CDK2 image.jpg|thumb|left|'''Crystal Structure of the human Cdk1 homolog, Cdk2''']]
Cdk1 is a small protein (approximately 34 kilodaltons), and is highly conserved. The human homolog of Cdk1, ''CDC2'', shares approximately 63% amino-acid identity with its yeast homolog. Furthermore, human ''CDC2'' is capable of rescuing fission yeast carrying a ''cdc2'' mutation.<ref name="pmid3553962"/><ref name="pmid8510751">{{cite journal | vauthors = De Bondt HL, Rosenblatt J, Jancarik J, Jones HD, Morgan DO, Kim SH | title = Crystal structure of cyclin-dependent kinase 2 | journal = Nature | volume = 363 | issue = 6430 | pages = 595–602 | date = June 1993 | pmid = 8510751 | doi = 10.1038/363595a0 | bibcode = 1993Natur.363..595D | s2cid = 4354370 }}</ref> Cdk1 is comprised mostly by the bare protein kinase motif, which other protein kinases share. Cdk1, like other kinases, contains a cleft in which [[Adenosine triphosphate|ATP]] fits. Substrates of Cdk1 bind near the mouth of the cleft, and Cdk1 residues catalyze the covalent bonding of the γ-phosphate to the oxygen of the [[hydroxyl]] serine/threonine of the substrate.
Cdk1 is a small protein (approximately 34 kilodaltons), and is highly conserved. The human homolog of Cdk1, ''CDK1'', shares approximately 63% amino-acid identity with its yeast homolog. Furthermore, human ''CDK1'' is capable of rescuing fission yeast carrying a ''cdc2'' mutation.<ref name="pmid3553962">{{cite journal | vauthors = Lee MG, Nurse P | title = Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2 | journal = Nature | volume = 327 | issue = 6117 | pages = 31–35 | date = Jun 1987 | pmid = 3553962 | doi = 10.1038/327031a0 | author-link2 = Paul Nurse | s2cid = 4300190 | bibcode = 1987Natur.327...31L | author-link1 = Melanie Lee }}</ref><ref name="pmid8510751">{{cite journal | vauthors = De Bondt HL, Rosenblatt J, Jancarik J, Jones HD, Morgan DO, Kim SH | title = Crystal structure of cyclin-dependent kinase 2 | journal = Nature | volume = 363 | issue = 6430 | pages = 595–602 | date = June 1993 | pmid = 8510751 | doi = 10.1038/363595a0 | s2cid = 4354370 | bibcode = 1993Natur.363..595D }}</ref> Cdk1 is comprised mostly by the bare protein kinase motif, which other protein kinases share. Cdk1, like other kinases, contains a cleft in which [[Adenosine triphosphate|ATP]] fits. Substrates of Cdk1 bind near the mouth of the cleft, and Cdk1 residues catalyze the covalent bonding of the γ-phosphate to the oxygen of the [[hydroxyl]] serine/threonine of the substrate.


In addition to this catalytic core, Cdk1, like other [[cyclin-dependent kinase]]s, contains a T-loop, which, in the absence of an interacting cyclin, prevents substrate binding to the Cdk1 active site. Cdk1 also contains a PSTAIRE helix, which, upon cyclin binding, moves and rearranges the active site, facilitating Cdk1 kinase activities.<ref name="pmid7630397">{{cite journal | vauthors = Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz J, Massagué J, Pavletich NP | title = Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex | journal = Nature | volume = 376 | issue = 6538 | pages = 313–320 | date = July 1995 | pmid = 7630397 | doi = 10.1038/376313a0 | bibcode = 1995Natur.376..313J | s2cid = 4361179 }}</ref>
In addition to this catalytic core, Cdk1, like other [[cyclin-dependent kinase]]s, contains a T-loop, which, in the absence of an interacting cyclin, prevents substrate binding to the Cdk1 active site. Cdk1 also contains a PSTAIRE helix, which, upon cyclin binding, moves and rearranges the active site, facilitating Cdk1 kinase activities.<ref name="pmid7630397">{{cite journal | vauthors = Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz J, Massagué J, Pavletich NP | title = Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex | journal = Nature | volume = 376 | issue = 6538 | pages = 313–320 | date = July 1995 | pmid = 7630397 | doi = 10.1038/376313a0 | s2cid = 4361179 | bibcode = 1995Natur.376..313J }}</ref>
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When bound to its cyclin partners, Cdk1 phosphorylation leads to cell cycle progression. Cdk1 activity is best understood in ''S. cerevisiae'', so Cdk1 ''S. cerevisiae'' activity is described here.
When bound to its cyclin partners, Cdk1 phosphorylation leads to cell cycle progression. Cdk1 activity is best understood in ''S. cerevisiae'', so Cdk1 ''S. cerevisiae'' activity is described here.


In the budding yeast, initial cell cycle entry is controlled by two regulatory complexes, SBF (SCB-binding factor) and MBF (MCB-binding factor). These two complexes control G<sub>1</sub>/S gene transcription; however, they are normally inactive. SBF is inhibited by the protein [[Whi5]]; however, when phosphorylated by Cln3-Cdk1, [[Whi5]] is ejected from the nucleus, allowing for transcription of the G<sub>1</sub>/S [[regulon]], which includes the G<sub>1</sub>/S cyclins Cln1,2.<ref name="pmid18633409">{{cite journal | vauthors = Skotheim JM, Di Talia S, Siggia ED, Cross FR | title = Positive feedback of G<sub>1</sub> cyclins ensures coherent cell cycle entry | journal = Nature | volume = 454 | issue = 7202 | pages = 291–296 | date = July 2008 | pmid = 18633409 | pmc = 2606905 | doi = 10.1038/nature07118 | bibcode = 2008Natur.454..291S }}</ref> G<sub>1</sub>/S cyclin-Cdk1 activity leads to preparation for S phase entry (e.g., duplication of centromeres or the spindle pole body), and a rise in the S cyclins (Clb5,6 in ''S. cerevisiae''). Clb5,6-Cdk1 complexes directly lead to replication origin initiation;<ref name="pmid10445023">{{cite journal | vauthors = Cross FR, Yuste-Rojas M, Gray S, Jacobson MD | title = Specialization and targeting of B-type cyclins | journal = Mol Cell | volume = 4 | issue = 1 | pages = 11–19 | date = July 1999 | pmid = 10445023 | doi = 10.1016/S1097-2765(00)80183-5 | doi-access = free }}</ref> however, they are inhibited by [[Sic1]], preventing premature S phase initiation.
In the budding yeast, initial cell cycle entry is controlled by two regulatory complexes, SBF (SCB-binding factor) and MBF (MCB-binding factor). These two complexes control G<sub>1</sub>/S gene transcription; however, they are normally inactive. SBF is inhibited by the protein [[Whi5]]; however, when phosphorylated by Cln3-Cdk1, [[Whi5]] is ejected from the nucleus, allowing for transcription of the G<sub>1</sub>/S [[regulon]], which includes the G<sub>1</sub>/S cyclins Cln1,2.<ref name="pmid18633409">{{cite journal | vauthors = Skotheim JM, Di Talia S, Siggia ED, Cross FR | title = Positive feedback of G1 cyclins ensures coherent cell cycle entry | journal = Nature | volume = 454 | issue = 7202 | pages = 291–296 | date = July 2008 | pmid = 18633409 | pmc = 2606905 | doi = 10.1038/nature07118 | bibcode = 2008Natur.454..291S }}</ref> G<sub>1</sub>/S cyclin-Cdk1 activity leads to preparation for S phase entry (e.g., duplication of centromeres or the spindle pole body), and a rise in the S cyclins (Clb5,6 in ''S. cerevisiae''). Clb5,6-Cdk1 complexes directly lead to replication origin initiation;<ref name="pmid10445023">{{cite journal | vauthors = Cross FR, Yuste-Rojas M, Gray S, Jacobson MD | title = Specialization and targeting of B-type cyclins | journal = Molecular Cell | volume = 4 | issue = 1 | pages = 11–19 | date = July 1999 | pmid = 10445023 | doi = 10.1016/S1097-2765(00)80183-5 | doi-access = free }}</ref> however, they are inhibited by [[Sic1]], preventing premature S phase initiation.


Cln1,2 and/or Clb5,6-Cdk1 complex activity leads to a sudden drop in Sic1 levels, allowing for coherent S phase entry. Finally, phosphorylation by M cyclins (e.g., Clb1, 2, 3 and 4) in complex with Cdk1 leads to spindle assembly and sister chromatid alignment. Cdk1 phosphorylation also leads to the activation of the ubiquitin-protein ligase APC<sup>Cdc20</sup>, an activation which allows for chromatid segregation and, furthermore, degradation of M-phase cyclins. This destruction of M cyclins leads to the final events of mitosis (e.g., spindle disassembly, mitotic exit).
Cln1,2 and/or Clb5,6-Cdk1 complex activity leads to a sudden drop in Sic1 levels, allowing for coherent S phase entry. Finally, phosphorylation by M cyclins (e.g., Clb1, 2, 3 and 4) in complex with Cdk1 leads to spindle assembly and sister chromatid alignment. Cdk1 phosphorylation also leads to the activation of the ubiquitin-protein ligase APC<sup>Cdc20</sup>, an activation which allows for chromatid segregation and, furthermore, degradation of M-phase cyclins. This destruction of M cyclins leads to the final events of mitosis (e.g., spindle disassembly, mitotic exit).
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== Regulation ==
== Regulation ==
Given its essential role in cell cycle progression, Cdk1 is highly regulated. Most obviously, Cdk1 is regulated by its binding with its cyclin partners. Cyclin binding alters access to the active site of Cdk1, allowing for Cdk1 activity; furthermore, cyclins impart specificity to Cdk1 activity. At least some cyclins contain a hydrophobic patch which may directly interact with substrates, conferring target specificity.<ref name="pmid10559988">{{cite journal | vauthors = Brown NR, Noble ME, Endicott JA, Johnson LN | title = The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases | journal = Nat. Cell Biol. | volume = 1 | issue = 7 | pages = 438–443 | date = November 1999 | pmid = 10559988 | doi = 10.1038/15674 | s2cid = 17988582 }}</ref> Furthermore, cyclins can target Cdk1 to particular subcellular locations.
Given its essential role in cell cycle progression, Cdk1 is highly regulated. Most obviously, Cdk1 is regulated by its binding with its cyclin partners. Cyclin binding alters access to the active site of Cdk1, allowing for Cdk1 activity; furthermore, cyclins impart specificity to Cdk1 activity. At least some cyclins contain a hydrophobic patch which may directly interact with substrates, conferring target specificity.<ref name="pmid10559988">{{cite journal | vauthors = Brown NR, Noble ME, Endicott JA, Johnson LN | title = The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases | journal = Nature Cell Biology | volume = 1 | issue = 7 | pages = 438–443 | date = November 1999 | pmid = 10559988 | doi = 10.1038/15674 | s2cid = 17988582 }}</ref> Furthermore, cyclins can target Cdk1 to particular subcellular locations.


In addition to regulation by cyclins, Cdk1 is regulated by phosphorylation. A conserved tyrosine (Tyr15 in humans) leads to inhibition of Cdk1; this phosphorylation is thought to alter ATP orientation, preventing efficient kinase activity. In S. pombe, for example, incomplete DNA synthesis may lead to stabilization of this phosphorylation, preventing mitotic progression.<ref name="pmid8939848">{{cite journal | vauthors = Elledge SJ | title = Cell cycle checkpoints: preventing an identity crisis | journal = Science | volume = 274 | issue = 5293 | pages = 1664–1672 | date = December 1996 | pmid = 8939848 | doi = 10.1126/science.274.5293.1664 | bibcode = 1996Sci...274.1664E | s2cid = 39235426 }}</ref> [[Wee1]], conserved among all eukaryotes phosphorylates Tyr15, whereas members of the Cdc25 family are phosphatases, counteracting this activity. The balance between the two is thought to help govern cell cycle progression. [[Wee1]] is controlled upstream by Cdr1, Cdr2, and [[Pom1]].
In addition to regulation by cyclins, Cdk1 is regulated by phosphorylation. A conserved tyrosine (Tyr15 in humans) leads to inhibition of Cdk1; this phosphorylation is thought to alter ATP orientation, preventing efficient kinase activity. In S. pombe, for example, incomplete DNA synthesis may lead to stabilization of this phosphorylation, preventing mitotic progression.<ref name="pmid8939848">{{cite journal | vauthors = Elledge SJ | title = Cell cycle checkpoints: preventing an identity crisis | journal = Science | volume = 274 | issue = 5293 | pages = 1664–1672 | date = December 1996 | pmid = 8939848 | doi = 10.1126/science.274.5293.1664 | s2cid = 39235426 | bibcode = 1996Sci...274.1664E }}</ref> [[Wee1]], conserved among all eukaryotes phosphorylates Tyr15, whereas members of the Cdc25 family are phosphatases, counteracting this activity. The balance between the two is thought to help govern cell cycle progression. [[Wee1]] is controlled upstream by Cdr1, Cdr2, and [[Pom1]].


Cdk1-cyclin complexes are also governed by direct binding of Cdk inhibitor proteins (CKIs). One such protein, already discussed, is Sic1. Sic1 is a stoichiometric inhibitor that binds directly to Clb5,6-Cdk1 complexes. Multisite phosphorylation, by Cdk1-Cln1/2, of Sic1 is thought to time Sic1 ubiquitination and destruction, and by extension, the timing of S-phase entry. Only until Sic1 inhibition is overcome can Clb5,6 activity occur and S phase initiation may begin.
Cdk1-cyclin complexes are also governed by direct binding of Cdk inhibitor proteins (CKIs). One such protein, already discussed, is Sic1. Sic1 is a stoichiometric inhibitor that binds directly to Clb5,6-Cdk1 complexes. Multisite phosphorylation, by Cdk1-Cln1/2, of Sic1 is thought to time Sic1 ubiquitination and destruction, and by extension, the timing of S-phase entry. Only until Sic1 inhibition is overcome can Clb5,6 activity occur and S phase initiation may begin.
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Cdk1 has been shown to [[Protein-protein interaction|interact]] with:
Cdk1 has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
{{div col|colwidth=20em}}
* [[Bcl-2|BCL2]],<ref name="pmid11774038">{{cite journal | vauthors = Pathan N, Aime-Sempe C, Kitada S, Basu A, Haldar S, Reed JC | title = Microtubule-targeting drugs induce bcl-2 phosphorylation and association with Pin1 | journal = Neoplasia | volume = 3 | issue = 6 | pages = 550–9 | year = 2001 | pmid = 11774038 | pmc = 1506558 | doi = 10.1038/sj.neo.7900213 }}</ref><ref name="pmid11326318">{{cite journal | vauthors = Pathan N, Aime-Sempe C, Kitada S, Haldar S, Reed JC | title = Microtubule-targeting drugs induce Bcl-2 phosphorylation and association with Pin1 | journal = Neoplasia | volume = 3 | issue = 1 | pages = 70–9 | year = 2001 | pmid = 11326318 | pmc = 1505024 | doi = 10.1038/sj.neo.7900131 }}</ref>
* [[Bcl-2|BCL2]],<ref name="pmid11774038">{{cite journal | vauthors = Pathan N, Aime-Sempe C, Kitada S, Basu A, Haldar S, Reed JC | title = Microtubule-targeting drugs induce bcl-2 phosphorylation and association with Pin1 | journal = Neoplasia | volume = 3 | issue = 6 | pages = 550–559 | year = 2001 | pmid = 11774038 | pmc = 1506558 | doi = 10.1038/sj.neo.7900213 }}</ref><ref name="pmid11326318">{{cite journal | vauthors = Pathan N, Aime-Sempe C, Kitada S, Haldar S, Reed JC | title = Microtubule-targeting drugs induce Bcl-2 phosphorylation and association with Pin1 | journal = Neoplasia | volume = 3 | issue = 1 | pages = 70–79 | year = 2001 | pmid = 11326318 | pmc = 1505024 | doi = 10.1038/sj.neo.7900131 }}</ref>
* [[Cyclin B1|CCNB1]],<ref name="pmid9891079">{{cite journal | vauthors = Shanahan F, Seghezzi W, Parry D, Mahony D, Lees E | title = Cyclin E associates with BAF155 and BRG1, components of the mammalian SWI-SNF complex, and alters the ability of BRG1 to induce growth arrest | journal = Mol. Cell. Biol. | volume = 19 | issue = 2 | pages = 1460–9 | date = February 1999 | pmid = 9891079 | pmc = 116074 | doi = 10.1128/mcb.19.2.1460}}</ref><ref name="pmid2570636">{{cite journal | vauthors = Pines J, Hunter T | title = Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2 | journal = Cell | volume = 58 | issue = 5 | pages = 833–846 | date = September 1989 | pmid = 2570636 | doi = 10.1016/0092-8674(89)90936-7 | s2cid = 20336733 }}</ref><ref name="pmid10716937">{{cite journal | vauthors = Kong M, Barnes EA, Ollendorff V, Donoghue DJ | title = Cyclin F regulates the nuclear localization of cyclin B1 through a cyclin-cyclin interaction | journal = EMBO J. | volume = 19 | issue = 6 | pages = 1378–1388 | date = March 2000 | pmid = 10716937 | pmc = 305678 | doi = 10.1093/emboj/19.6.1378 }}</ref>
* [[Cyclin B1|CCNB1]],<ref name="pmid9891079">{{cite journal | vauthors = Shanahan F, Seghezzi W, Parry D, Mahony D, Lees E | title = Cyclin E associates with BAF155 and BRG1, components of the mammalian SWI-SNF complex, and alters the ability of BRG1 to induce growth arrest | journal = Molecular and Cellular Biology | volume = 19 | issue = 2 | pages = 1460–1469 | date = February 1999 | pmid = 9891079 | pmc = 116074 | doi = 10.1128/mcb.19.2.1460 }}</ref><ref name="pmid2570636">{{cite journal | vauthors = Pines J, Hunter T | title = Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2 | journal = Cell | volume = 58 | issue = 5 | pages = 833–846 | date = September 1989 | pmid = 2570636 | doi = 10.1016/0092-8674(89)90936-7 | s2cid = 20336733 }}</ref><ref name="pmid10716937">{{cite journal | vauthors = Kong M, Barnes EA, Ollendorff V, Donoghue DJ | title = Cyclin F regulates the nuclear localization of cyclin B1 through a cyclin-cyclin interaction | journal = The EMBO Journal | volume = 19 | issue = 6 | pages = 1378–1388 | date = March 2000 | pmid = 10716937 | pmc = 305678 | doi = 10.1093/emboj/19.6.1378 }}</ref>
* [[Cyclin E1|CCNE1]],<ref name=pmid9891079/><ref name="pmid1388288">{{cite journal | vauthors = Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, Nishimoto T, Morgan DO, Franza BR, Roberts JM | title = Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle | journal = Science | volume = 257 | issue = 5077 | pages = 1689–1694 | date = September 1992 | pmid = 1388288 | doi = 10.1126/science.1388288 | bibcode = 1992Sci...257.1689K }}</ref>
* [[Cyclin E1|CCNE1]],<ref name=pmid9891079/><ref name="pmid1388288">{{cite journal | vauthors = Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, Nishimoto T, Morgan DO, Franza BR, Roberts JM | title = Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle | journal = Science | volume = 257 | issue = 5077 | pages = 1689–1694 | date = September 1992 | pmid = 1388288 | doi = 10.1126/science.1388288 | bibcode = 1992Sci...257.1689K }}</ref>
* [[CDKN3]]<ref name="pmid8127873">{{cite journal | vauthors = Hannon GJ, Casso D, Beach D | title = KAP: a dual specificity phosphatase that interacts with cyclin-dependent kinases | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 91 | issue = 5 | pages = 1731–1735 | date = March 1994 | pmid = 8127873 | pmc = 43237 | doi = 10.1073/pnas.91.5.1731 | bibcode = 1994PNAS...91.1731H | doi-access = free }}</ref><ref name="pmid8242750">{{cite journal | vauthors = Gyuris J, Golemis E, Chertkov H, Brent R | title = Cdi1, a human G1 and S phase protein phosphatase that associates with Cdk2 | journal = Cell | volume = 75 | issue = 4 | pages = 791–803 | date = November 1993 | pmid = 8242750 | doi = 10.1016/0092-8674(93)90498-F | doi-access = free }}</ref>
* [[CDKN3]]<ref name="pmid8127873">{{cite journal | vauthors = Hannon GJ, Casso D, Beach D | title = KAP: a dual specificity phosphatase that interacts with cyclin-dependent kinases | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 5 | pages = 1731–1735 | date = March 1994 | pmid = 8127873 | pmc = 43237 | doi = 10.1073/pnas.91.5.1731 | doi-access = free | bibcode = 1994PNAS...91.1731H }}</ref><ref name="pmid8242750">{{cite journal | vauthors = Gyuris J, Golemis E, Chertkov H, Brent R | title = Cdi1, a human G1 and S phase protein phosphatase that associates with Cdk2 | journal = Cell | volume = 75 | issue = 4 | pages = 791–803 | date = November 1993 | pmid = 8242750 | doi = 10.1016/0092-8674(93)90498-F | doi-access = free }}</ref>
* [[DAB2]],<ref name="pmid12881709">{{cite journal | vauthors = He J, Xu J, Xu XX, Hall RA | title = Cell cycle-dependent phosphorylation of Disabled-2 by cdc2 | journal = Oncogene | volume = 22 | issue = 29 | pages = 4524–4530 | date = July 2003 | pmid = 12881709 | doi = 10.1038/sj.onc.1206767 | doi-access = free }}</ref>
* [[DAB2]],<ref name="pmid12881709">{{cite journal | vauthors = He J, Xu J, Xu XX, Hall RA | title = Cell cycle-dependent phosphorylation of Disabled-2 by cdc2 | journal = Oncogene | volume = 22 | issue = 29 | pages = 4524–4530 | date = July 2003 | pmid = 12881709 | doi = 10.1038/sj.onc.1206767 | doi-access = free }}</ref>
* [[Fanconi anemia, complementation group C|FANCC]],<ref name="pmid14499622">{{cite journal | vauthors = Reuter TY, Medhurst AL, Waisfisz Q, Zhi Y, Herterich S, Hoehn H, Gross HJ, Joenje H, Hoatlin ME, Mathew CG, Huber PA | title = Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport | journal = Exp. Cell Res. | volume = 289 | issue = 2 | pages = 211–221 | date = October 2003 | pmid = 14499622 | doi = 10.1016/S0014-4827(03)00261-1 }}</ref><ref name="pmid9242535">{{cite journal | vauthors = Kupfer GM, Yamashita T, Naf D, Suliman A, Asano S, D'Andrea AD | title = The Fanconi anemia polypeptide, FAC, binds to the cyclin-dependent kinase, cdc2 | journal = Blood | volume = 90 | issue = 3 | pages = 1047–54 | date = August 1997 | pmid = 9242535 | doi = 10.1182/blood.V90.3.1047| doi-access = free }}</ref>
* [[Fanconi anemia, complementation group C|FANCC]],<ref name="pmid14499622">{{cite journal | vauthors = Reuter TY, Medhurst AL, Waisfisz Q, Zhi Y, Herterich S, Hoehn H, Gross HJ, Joenje H, Hoatlin ME, Mathew CG, Huber PA | title = Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport | journal = Experimental Cell Research | volume = 289 | issue = 2 | pages = 211–221 | date = October 2003 | pmid = 14499622 | doi = 10.1016/S0014-4827(03)00261-1 }}</ref><ref name="pmid9242535">{{cite journal | vauthors = Kupfer GM, Yamashita T, Naf D, Suliman A, Asano S, D'Andrea AD | title = The Fanconi anemia polypeptide, FAC, binds to the cyclin-dependent kinase, cdc2 | journal = Blood | volume = 90 | issue = 3 | pages = 1047–1054 | date = August 1997 | pmid = 9242535 | doi = 10.1182/blood.V90.3.1047 | doi-access = free }}</ref>
* [[GADD45A]],<ref name="pmid10362260">{{cite journal | vauthors = Zhan Q, Antinore MJ, Wang XW, Carrier F, Smith ML, Harris CC, Fornace AJ | title = Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45 | journal = Oncogene | volume = 18 | issue = 18 | pages = 2892–2900 | date = May 1999 | pmid = 10362260 | doi = 10.1038/sj.onc.1202667 | doi-access = free }}</ref><ref name="pmid10747892">{{cite journal | vauthors = Jin S, Antinore MJ, Lung FD, Dong X, Zhao H, Fan F, Colchagie AB, Blanck P, Roller PP, Fornace AJ, Zhan Q | title = The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression | journal = J. Biol. Chem. | volume = 275 | issue = 22 | pages = 16602–16608 | date = June 2000 | pmid = 10747892 | doi = 10.1074/jbc.M000284200 | doi-access = free }}</ref><ref name="pmid10973963">{{cite journal | vauthors = Yang Q, Manicone A, Coursen JD, Linke SP, Nagashima M, Forgues M, Wang XW | title = Identification of a functional domain in a GADD45-mediated G2/M checkpoint | journal = J. Biol. Chem. | volume = 275 | issue = 47 | pages = 36892–36898 | date = November 2000 | pmid = 10973963 | doi = 10.1074/jbc.M005319200 | doi-access = free }}</ref><ref name="pmid12124778">{{cite journal | vauthors = Vairapandi M, Balliet AG, Hoffman B, Liebermann DA | title = GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress | journal = J. Cell. Physiol. | volume = 192 | issue = 3 | pages = 327–338 | date = September 2002 | pmid = 12124778 | doi = 10.1002/jcp.10140 | s2cid = 19138273 }}</ref>
* [[GADD45A]],<ref name="pmid10362260">{{cite journal | vauthors = Zhan Q, Antinore MJ, Wang XW, Carrier F, Smith ML, Harris CC, Fornace AJ | title = Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45 | journal = Oncogene | volume = 18 | issue = 18 | pages = 2892–2900 | date = May 1999 | pmid = 10362260 | doi = 10.1038/sj.onc.1202667 | doi-access = free }}</ref><ref name="pmid10747892">{{cite journal | vauthors = Jin S, Antinore MJ, Lung FD, Dong X, Zhao H, Fan F, Colchagie AB, Blanck P, Roller PP, Fornace AJ, Zhan Q | title = The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression | journal = The Journal of Biological Chemistry | volume = 275 | issue = 22 | pages = 16602–16608 | date = June 2000 | pmid = 10747892 | doi = 10.1074/jbc.M000284200 | doi-access = free }}</ref><ref name="pmid10973963">{{cite journal | vauthors = Yang Q, Manicone A, Coursen JD, Linke SP, Nagashima M, Forgues M, Wang XW | title = Identification of a functional domain in a GADD45-mediated G2/M checkpoint | journal = The Journal of Biological Chemistry | volume = 275 | issue = 47 | pages = 36892–36898 | date = November 2000 | pmid = 10973963 | doi = 10.1074/jbc.M005319200 | doi-access = free }}</ref><ref name="pmid12124778">{{cite journal | vauthors = Vairapandi M, Balliet AG, Hoffman B, Liebermann DA | title = GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress | journal = Journal of Cellular Physiology | volume = 192 | issue = 3 | pages = 327–338 | date = September 2002 | pmid = 12124778 | doi = 10.1002/jcp.10140 | s2cid = 19138273 }}</ref>
*[[LATS1]],<ref name="pmid9988268">{{cite journal | vauthors = Tao W, Zhang S, Turenchalk GS, Stewart RA, St John MA, Chen W, Xu T | title = Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity | journal = Nat. Genet. | volume = 21 | issue = 2 | pages = 177–181 | date = February 1999 | pmid = 9988268 | doi = 10.1038/5960 | s2cid = 32090556 }}</ref>
*[[LATS1]],<ref name="pmid9988268">{{cite journal | vauthors = Tao W, Zhang S, Turenchalk GS, Stewart RA, St John MA, Chen W, Xu T | title = Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity | journal = Nature Genetics | volume = 21 | issue = 2 | pages = 177–181 | date = February 1999 | pmid = 9988268 | doi = 10.1038/5960 | s2cid = 32090556 }}</ref>
* [[LYN]],<ref name="pmid8051175">{{cite journal | vauthors = Kharbanda S, Yuan ZM, Rubin E, Weichselbaum R, Kufe D | title = Activation of Src-like p56/p53lyn tyrosine kinase by ionizing radiation | journal = J. Biol. Chem. | volume = 269 | issue = 32 | pages = 20739–43 | date = August 1994 | doi = 10.1016/S0021-9258(17)32054-9 | pmid = 8051175 | doi-access = free }}</ref><ref name="pmid8910336">{{cite journal | vauthors = Pathan NI, Geahlen RL, Harrison ML | title = The protein-tyrosine kinase Lck associates with and is phosphorylated by Cdc2 | journal = J. Biol. Chem. | volume = 271 | issue = 44 | pages = 27517–27523 | date = November 1996 | pmid = 8910336 | doi = 10.1074/jbc.271.44.27517 | doi-access = free }}</ref>
* [[LYN]],<ref name="pmid8051175">{{cite journal | vauthors = Kharbanda S, Yuan ZM, Rubin E, Weichselbaum R, Kufe D | title = Activation of Src-like p56/p53lyn tyrosine kinase by ionizing radiation | journal = The Journal of Biological Chemistry | volume = 269 | issue = 32 | pages = 20739–20743 | date = August 1994 | pmid = 8051175 | doi = 10.1016/S0021-9258(17)32054-9 | doi-access = free }}</ref><ref name="pmid8910336">{{cite journal | vauthors = Pathan NI, Geahlen RL, Harrison ML | title = The protein-tyrosine kinase Lck associates with and is phosphorylated by Cdc2 | journal = The Journal of Biological Chemistry | volume = 271 | issue = 44 | pages = 27517–27523 | date = November 1996 | pmid = 8910336 | doi = 10.1074/jbc.271.44.27517 | doi-access = free }}</ref>
* [[P53]],<ref name="pmid10884347">{{cite journal | vauthors = Luciani MG, Hutchins JR, Zheleva D, Hupp TR | title = The C-terminal regulatory domain of p53 contains a functional docking site for cyclin A | journal = J. Mol. Biol. | volume = 300 | issue = 3 | pages = 503–518 | date = July 2000 | pmid = 10884347 | doi = 10.1006/jmbi.2000.3830 }}</ref><ref name="pmid11327730">{{cite journal | vauthors = Ababneh M, Götz C, Montenarh M | title = Downregulation of the cdc2/cyclin B protein kinase activity by binding of p53 to p34(cdc2) | journal = Biochem. Biophys. Res. Commun. | volume = 283 | issue = 2 | pages = 507–512 | date = May 2001 | pmid = 11327730 | doi = 10.1006/bbrc.2001.4792 }}</ref> and
* [[P53]],<ref name="pmid10884347">{{cite journal | vauthors = Luciani MG, Hutchins JR, Zheleva D, Hupp TR | title = The C-terminal regulatory domain of p53 contains a functional docking site for cyclin A | journal = Journal of Molecular Biology | volume = 300 | issue = 3 | pages = 503–518 | date = July 2000 | pmid = 10884347 | doi = 10.1006/jmbi.2000.3830 }}</ref><ref name="pmid11327730">{{cite journal | vauthors = Ababneh M, Götz C, Montenarh M | title = Downregulation of the cdc2/cyclin B protein kinase activity by binding of p53 to p34(cdc2) | journal = Biochemical and Biophysical Research Communications | volume = 283 | issue = 2 | pages = 507–512 | date = May 2001 | pmid = 11327730 | doi = 10.1006/bbrc.2001.4792 }}</ref> and
* [[Ubiquitin C|UBC]].<ref name="pmid18655026">{{cite journal | vauthors = Tan F, Lu L, Cai Y, Wang J, Xie Y, Wang L, Gong Y, Xu BE, Wu J, Luo Y, Qiang B, Yuan J, Sun X, Peng X | title = Proteomic analysis of ubiquitinated proteins in normal hepatocyte cell line Chang liver cells | journal = Proteomics | volume = 8 | issue = 14 | pages = 2885–2896 | date = July 2008 | pmid = 18655026 | doi = 10.1002/pmic.200700887 | s2cid = 25586938 }}</ref>
* [[Ubiquitin C|UBC]].<ref name="pmid18655026">{{cite journal | vauthors = Tan F, Lu L, Cai Y, Wang J, Xie Y, Wang L, Gong Y, Xu BE, Wu J, Luo Y, Qiang B, Yuan J, Sun X, Peng X | title = Proteomic analysis of ubiquitinated proteins in normal hepatocyte cell line Chang liver cells | journal = Proteomics | volume = 8 | issue = 14 | pages = 2885–2896 | date = July 2008 | pmid = 18655026 | doi = 10.1002/pmic.200700887 | s2cid = 25586938 }}</ref>
{{Div col end}}
{{Div col end}}
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== Further reading ==
== Further reading ==
{{refbegin|35em}}
{{refbegin|35em}}
* {{cite journal | vauthors = Draetta G, Eckstein J | title = Cdc25 protein phosphatases in cell proliferation | journal = Biochim. Biophys. Acta | volume = 1332 | issue = 2 | pages = M53–63 | year = 1997 | pmid = 9141461 | doi = 10.1016/S0304-419X(96)00049-2 }}
* {{cite journal | vauthors = Draetta G, Eckstein J | title = Cdc25 protein phosphatases in cell proliferation | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 1332 | issue = 2 | pages = M53–M63 | date = April 1997 | pmid = 9141461 | doi = 10.1016/S0304-419X(96)00049-2 }}
* {{cite journal | vauthors = Kino T, Pavlakis GN | title = Partner molecules of accessory protein Vpr of the human immunodeficiency virus type 1 | journal = DNA Cell Biol. | volume = 23 | issue = 4 | pages = 193–205 | year = 2004 | pmid = 15142377 | doi = 10.1089/104454904773819789 | url = https://zenodo.org/record/1235217 }}
* {{cite journal | vauthors = Kino T, Pavlakis GN | title = Partner molecules of accessory protein Vpr of the human immunodeficiency virus type 1 | journal = DNA and Cell Biology | volume = 23 | issue = 4 | pages = 193–205 | date = April 2004 | pmid = 15142377 | doi = 10.1089/104454904773819789 }}
* {{cite journal | vauthors = Kino T, Chrousos GP | title = Human immunodeficiency virus type-1 accessory protein Vpr: a causative agent of the AIDS-related insulin resistance/lipodystrophy syndrome? | journal = Ann. N. Y. Acad. Sci. | volume = 1024 | issue = 1| pages = 153–167 | year = 2004 | pmid = 15265780 | doi = 10.1196/annals.1321.013 | url = https://zenodo.org/record/1235880 | bibcode = 2004NYASA1024..153K | s2cid = 23655886 }}
* {{cite journal | vauthors = Kino T, Chrousos GP | title = Human immunodeficiency virus type-1 accessory protein Vpr: a causative agent of the AIDS-related insulin resistance/lipodystrophy syndrome? | journal = Annals of the New York Academy of Sciences | volume = 1024 | issue = 1 | pages = 153–167 | date = June 2004 | pmid = 15265780 | doi = 10.1196/annals.1321.013 | s2cid = 23655886 | bibcode = 2004NYASA1024..153K }}
* {{cite journal | vauthors = Zhao LJ, Zhu H | title = Structure and function of HIV-1 auxiliary regulatory protein Vpr: novel clues to drug design | journal = Curr. Drug Targets Immune Endocr. Metabol. Disord. | volume = 4 | issue = 4 | pages = 265–275 | year = 2005 | pmid = 15578977 | doi = 10.2174/1568008043339668 }}
* {{cite journal | vauthors = Zhao LJ, Zhu H | title = Structure and function of HIV-1 auxiliary regulatory protein Vpr: novel clues to drug design | journal = Current Drug Targets. Immune, Endocrine and Metabolic Disorders | volume = 4 | issue = 4 | pages = 265–275 | date = December 2004 | pmid = 15578977 | doi = 10.2174/1568008043339668 }}
* {{cite journal | vauthors = Le Rouzic E, Benichou S | title = The Vpr protein from HIV-1: distinct roles along the viral life cycle | journal = Retrovirology | volume = 2 | pages = 11 | year = 2006 | pmid = 15725353 | pmc = 554975 | doi = 10.1186/1742-4690-2-11 }}
* {{cite journal | vauthors = Le Rouzic E, Benichou S | title = The Vpr protein from HIV-1: distinct roles along the viral life cycle | journal = Retrovirology | volume = 2 | pages = 11 | date = February 2005 | pmid = 15725353 | pmc = 554975 | doi = 10.1186/1742-4690-2-11 | doi-access = free }}
* {{cite journal | vauthors = Zhao RY, Elder RT | title = Viral infections and cell cycle G2/M regulation | journal = Cell Res. | volume = 15 | issue = 3 | pages = 143–149 | year = 2005 | pmid = 15780175 | doi = 10.1038/sj.cr.7290279 | doi-access = free }}
* {{cite journal | vauthors = Zhao RY, Elder RT | title = Viral infections and cell cycle G2/M regulation | journal = Cell Research | volume = 15 | issue = 3 | pages = 143–149 | date = March 2005 | pmid = 15780175 | doi = 10.1038/sj.cr.7290279 | doi-access = free }}
* {{cite journal | vauthors = Zhao RY, Bukrinsky M, Elder RT | title = HIV-1 viral protein R (Vpr) & host cellular responses | journal = Indian J. Med. Res. | volume = 121 | issue = 4 | pages = 270–86 | year = 2005 | pmid = 15817944 }}
* {{cite journal | vauthors = Zhao RY, Bukrinsky M, Elder RT | title = HIV-1 viral protein R (Vpr) & host cellular responses | journal = The Indian Journal of Medical Research | volume = 121 | issue = 4 | pages = 270–286 | date = April 2005 | pmid = 15817944 }}
* {{cite journal | vauthors = Kaldis P, Aleem E | title = Cell cycle sibling rivalry: Cdc2 vs. Cdk2 | journal = Cell Cycle | volume = 4 | issue = 11 | pages = 1491–1494 | year = 2007 | pmid = 16258277 | doi = 10.4161/cc.4.11.2124 | doi-access = free }}
* {{cite journal | vauthors = Kaldis P, Aleem E | title = Cell cycle sibling rivalry: Cdc2 vs. Cdk2 | journal = Cell Cycle | volume = 4 | issue = 11 | pages = 1491–1494 | date = November 2005 | pmid = 16258277 | doi = 10.4161/cc.4.11.2124 | doi-access = free }}
* {{cite journal | vauthors = Li L, Li HS, Pauza CD, Bukrinsky M, Zhao RY | title = Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions | journal = Cell Res. | volume = 15 | issue = 11–12 | pages = 923–934 | year = 2006 | pmid = 16354571 | doi = 10.1038/sj.cr.7290370 | doi-access = free }}
* {{cite journal | vauthors = Li L, Li HS, Pauza CD, Bukrinsky M, Zhao RY | title = Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions | journal = Cell Research | volume = 15 | issue = 11–12 | pages = 923–934 | year = 2006 | pmid = 16354571 | doi = 10.1038/sj.cr.7290370 | doi-access = free }}
* {{cite journal | vauthors = Rietbrock N, Keller F | title = [Biologic availability and "1st pass" effect of drugs] | journal = Fortschr. Med. | volume = 95 | issue = 28 | pages = 1765–6, 1774–80 | year = 1977 | pmid = 914146 }}
* {{cite journal | vauthors = Rietbrock N, Keller F | title = [Biologic availability and "1st pass" effect of drugs] | journal = Fortschritte der Medizin | volume = 95 | issue = 28 | pages = 1765–6, 1774–80 | date = July 1977 | pmid = 914146 }}
* {{cite journal | vauthors = Azzi L, Meijer L, Reed SI, Pidikiti R, Tung HY | title = Interaction between the cell-cycle-control proteins p34cdc2 and p9CKShs2. Evidence for two cooperative binding domains in p9CKShs2 | journal = Eur. J. Biochem. | volume = 203 | issue = 3 | pages = 353–360 | year = 1992 | pmid = 1310466 | doi = 10.1111/j.1432-1033.1992.tb16557.x | doi-access = free }}
* {{cite journal | vauthors = Azzi L, Meijer L, Reed SI, Pidikiti R, Tung HY | title = Interaction between the cell-cycle-control proteins p34cdc2 and p9CKShs2. Evidence for two cooperative binding domains in p9CKShs2 | journal = European Journal of Biochemistry | volume = 203 | issue = 3 | pages = 353–360 | date = February 1992 | pmid = 1310466 | doi = 10.1111/j.1432-1033.1992.tb16557.x | doi-access = free }}
* {{cite journal | vauthors = Dutta A, Stillman B | title = cdc2 family kinases phosphorylate a human cell DNA replication factor, RPA, and activate DNA replication | journal = EMBO J. | volume = 11 | issue = 6 | pages = 2189–99 | year = 1992 | pmid = 1318195 | pmc = 556686 | doi = 10.1002/j.1460-2075.1992.tb05278.x}}
* {{cite journal | vauthors = Dutta A, Stillman B | title = cdc2 family kinases phosphorylate a human cell DNA replication factor, RPA, and activate DNA replication | journal = The EMBO Journal | volume = 11 | issue = 6 | pages = 2189–2199 | date = June 1992 | pmid = 1318195 | pmc = 556686 | doi = 10.1002/j.1460-2075.1992.tb05278.x }}
* {{cite journal | vauthors = Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, Nishimoto T, Morgan DO, Franza BR, Roberts JM | title = Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle | journal = Science | volume = 257 | issue = 5077 | pages = 1689–1694 | year = 1992 | pmid = 1388288 | doi = 10.1126/science.1388288 | bibcode = 1992Sci...257.1689K }}
* {{cite journal | vauthors = Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, Nishimoto T, Morgan DO, Franza BR, Roberts JM | title = Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle | journal = Science | volume = 257 | issue = 5077 | pages = 1689–1694 | date = September 1992 | pmid = 1388288 | doi = 10.1126/science.1388288 | bibcode = 1992Sci...257.1689K }}
* {{cite journal | vauthors = Russo GL, Vandenberg MT, Yu IJ, Bae YS, Franza BR, Marshak DR | title = Casein kinase II phosphorylates p34cdc2 kinase in G1 phase of the HeLa cell division cycle | journal = J. Biol. Chem. | volume = 267 | issue = 28 | pages = 20317–25 | year = 1992 | doi = 10.1016/S0021-9258(19)88704-5 | pmid = 1400350 | doi-access = free }}
* {{cite journal | vauthors = Russo GL, Vandenberg MT, Yu IJ, Bae YS, Franza BR, Marshak DR | title = Casein kinase II phosphorylates p34cdc2 kinase in G1 phase of the HeLa cell division cycle | journal = The Journal of Biological Chemistry | volume = 267 | issue = 28 | pages = 20317–20325 | date = October 1992 | pmid = 1400350 | doi = 10.1016/S0021-9258(19)88704-5 | doi-access = free }}
* {{cite journal | vauthors = Rubinfeld B, Crosier WJ, Albert I, Conroy L, Clark R, McCormick F, Polakis P | title = Localization of the rap1GAP catalytic domain and sites of phosphorylation by mutational analysis | journal = Mol. Cell. Biol. | volume = 12 | issue = 10 | pages = 4634–42 | year = 1992 | pmid = 1406653 | pmc = 360390 | doi = 10.1128/MCB.12.10.4634}}
* {{cite journal | vauthors = Rubinfeld B, Crosier WJ, Albert I, Conroy L, Clark R, McCormick F, Polakis P | title = Localization of the rap1GAP catalytic domain and sites of phosphorylation by mutational analysis | journal = Molecular and Cellular Biology | volume = 12 | issue = 10 | pages = 4634–4642 | date = October 1992 | pmid = 1406653 | pmc = 360390 | doi = 10.1128/MCB.12.10.4634 }}
* {{cite journal | vauthors = van der Sluijs P, Hull M, Huber LA, Mâle P, Goud B, Mellman I | title = Reversible phosphorylation--dephosphorylation determines the localization of rab4 during the cell cycle | journal = EMBO J. | volume = 11 | issue = 12 | pages = 4379–89 | year = 1992 | pmid = 1425574 | pmc = 557012 | doi = 10.1002/j.1460-2075.1992.tb05538.x}}
* {{cite journal | vauthors = van der Sluijs P, Hull M, Huber LA, Mâle P, Goud B, Mellman I | title = Reversible phosphorylation--dephosphorylation determines the localization of rab4 during the cell cycle | journal = The EMBO Journal | volume = 11 | issue = 12 | pages = 4379–4389 | date = December 1992 | pmid = 1425574 | pmc = 557012 | doi = 10.1002/j.1460-2075.1992.tb05538.x }}
* {{cite journal | vauthors = Seth A, Alvarez E, Gupta S, Davis RJ | title = A phosphorylation site located in the NH2-terminal domain of c-Myc increases transactivation of gene expression | journal = J. Biol. Chem. | volume = 266 | issue = 35 | pages = 23521–4 | year = 1992 | doi = 10.1016/S0021-9258(18)54312-X | pmid = 1748630 | doi-access = free }}
* {{cite journal | vauthors = Seth A, Alvarez E, Gupta S, Davis RJ | title = A phosphorylation site located in the NH2-terminal domain of c-Myc increases transactivation of gene expression | journal = The Journal of Biological Chemistry | volume = 266 | issue = 35 | pages = 23521–23524 | date = December 1991 | pmid = 1748630 | doi = 10.1016/S0021-9258(18)54312-X | doi-access = free }}
* {{cite journal | vauthors = Lees JA, Buchkovich KJ, Marshak DR, Anderson CW, Harlow E | title = The retinoblastoma protein is phosphorylated on multiple sites by human cdc2 | journal = EMBO J. | volume = 10 | issue = 13 | pages = 4279–90 | year = 1992 | pmid = 1756735 | pmc = 453181 | doi = 10.1002/j.1460-2075.1991.tb05006.x}}
* {{cite journal | vauthors = Lees JA, Buchkovich KJ, Marshak DR, Anderson CW, Harlow E | title = The retinoblastoma protein is phosphorylated on multiple sites by human cdc2 | journal = The EMBO Journal | volume = 10 | issue = 13 | pages = 4279–4290 | date = December 1991 | pmid = 1756735 | pmc = 453181 | doi = 10.1002/j.1460-2075.1991.tb05006.x }}
* {{cite journal | vauthors = Nazarenko SA, Ostroverhova NV, Spurr NK | title = Regional assignment of the human cell cycle control gene CDC2 to chromosome 10q21 by in situ hybridization | journal = Hum. Genet. | volume = 87 | issue = 5 | pages = 621–2 | year = 1991 | pmid = 1916766 | doi = 10.1007/BF00209025 | s2cid = 25673088 }}
* {{cite journal | vauthors = Nazarenko SA, Ostroverhova NV, Spurr NK | title = Regional assignment of the human cell cycle control gene CDC2 to chromosome 10q21 by in situ hybridization | journal = Human Genetics | volume = 87 | issue = 5 | pages = 621–622 | date = September 1991 | pmid = 1916766 | doi = 10.1007/BF00209025 | s2cid = 25673088 }}
* {{cite journal | vauthors = Nissen MS, Langan TA, Reeves R | title = Phosphorylation by cdc2 kinase modulates DNA binding activity of high mobility group I nonhistone chromatin protein | journal = J. Biol. Chem. | volume = 266 | issue = 30 | pages = 19945–52 | year = 1991 | doi = 10.1016/S0021-9258(18)54874-2 | pmid = 1939057 | doi-access = free }}
* {{cite journal | vauthors = Nissen MS, Langan TA, Reeves R | title = Phosphorylation by cdc2 kinase modulates DNA binding activity of high mobility group I nonhistone chromatin protein | journal = The Journal of Biological Chemistry | volume = 266 | issue = 30 | pages = 19945–19952 | date = October 1991 | pmid = 1939057 | doi = 10.1016/S0021-9258(18)54874-2 | doi-access = free }}
{{refend}}
{{refend}}


Latest revision as of 12:38, 29 August 2024

CDK1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCDK1, CDC2, CDC28A, P34CDC2, cyclin-dependent kinase 1, cyclin dependent kinase 1
External IDsOMIM: 116940; MGI: 88351; HomoloGene: 68203; GeneCards: CDK1; OMA:CDK1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

983

12534

Ensembl

ENSG00000170312

ENSMUSG00000019942

UniProt

P06493

P11440

RefSeq (mRNA)

NM_007659

RefSeq (protein)

NP_001163877
NP_001163878
NP_001307847
NP_001777
NP_203698

NP_031685

Location (UCSC)Chr 10: 60.78 – 60.79 MbChr 10: 69.17 – 69.19 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog is a highly conserved protein that functions as a serine/threonine protein kinase, and is a key player in cell cycle regulation.[5] It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S. pombe, where it is encoded by genes cdc28 and cdc2, respectively.[6] With its cyclin partners, Cdk1 forms complexes that phosphorylate a variety of target substrates (over 75 have been identified in budding yeast); phosphorylation of these proteins leads to cell cycle progression.[7]

Structure

[edit]
Crystal Structure of the human Cdk1 homolog, Cdk2

Cdk1 is a small protein (approximately 34 kilodaltons), and is highly conserved. The human homolog of Cdk1, CDK1, shares approximately 63% amino-acid identity with its yeast homolog. Furthermore, human CDK1 is capable of rescuing fission yeast carrying a cdc2 mutation.[8][9] Cdk1 is comprised mostly by the bare protein kinase motif, which other protein kinases share. Cdk1, like other kinases, contains a cleft in which ATP fits. Substrates of Cdk1 bind near the mouth of the cleft, and Cdk1 residues catalyze the covalent bonding of the γ-phosphate to the oxygen of the hydroxyl serine/threonine of the substrate.

In addition to this catalytic core, Cdk1, like other cyclin-dependent kinases, contains a T-loop, which, in the absence of an interacting cyclin, prevents substrate binding to the Cdk1 active site. Cdk1 also contains a PSTAIRE helix, which, upon cyclin binding, moves and rearranges the active site, facilitating Cdk1 kinase activities.[10]

Function

[edit]
Fig. 1 The diagram shows the role of Cdk1 in progression through the S. cerevisiae cell cycle. Cln3-Cdk1 leads to Cln1,2-Cdk1 activity, eventually resulting in Clb5,6-Cdk1 activity and then Clb1-4-Cdk1 activity.[5]

When bound to its cyclin partners, Cdk1 phosphorylation leads to cell cycle progression. Cdk1 activity is best understood in S. cerevisiae, so Cdk1 S. cerevisiae activity is described here.

In the budding yeast, initial cell cycle entry is controlled by two regulatory complexes, SBF (SCB-binding factor) and MBF (MCB-binding factor). These two complexes control G1/S gene transcription; however, they are normally inactive. SBF is inhibited by the protein Whi5; however, when phosphorylated by Cln3-Cdk1, Whi5 is ejected from the nucleus, allowing for transcription of the G1/S regulon, which includes the G1/S cyclins Cln1,2.[11] G1/S cyclin-Cdk1 activity leads to preparation for S phase entry (e.g., duplication of centromeres or the spindle pole body), and a rise in the S cyclins (Clb5,6 in S. cerevisiae). Clb5,6-Cdk1 complexes directly lead to replication origin initiation;[12] however, they are inhibited by Sic1, preventing premature S phase initiation.

Cln1,2 and/or Clb5,6-Cdk1 complex activity leads to a sudden drop in Sic1 levels, allowing for coherent S phase entry. Finally, phosphorylation by M cyclins (e.g., Clb1, 2, 3 and 4) in complex with Cdk1 leads to spindle assembly and sister chromatid alignment. Cdk1 phosphorylation also leads to the activation of the ubiquitin-protein ligase APCCdc20, an activation which allows for chromatid segregation and, furthermore, degradation of M-phase cyclins. This destruction of M cyclins leads to the final events of mitosis (e.g., spindle disassembly, mitotic exit).

Regulation

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Given its essential role in cell cycle progression, Cdk1 is highly regulated. Most obviously, Cdk1 is regulated by its binding with its cyclin partners. Cyclin binding alters access to the active site of Cdk1, allowing for Cdk1 activity; furthermore, cyclins impart specificity to Cdk1 activity. At least some cyclins contain a hydrophobic patch which may directly interact with substrates, conferring target specificity.[13] Furthermore, cyclins can target Cdk1 to particular subcellular locations.

In addition to regulation by cyclins, Cdk1 is regulated by phosphorylation. A conserved tyrosine (Tyr15 in humans) leads to inhibition of Cdk1; this phosphorylation is thought to alter ATP orientation, preventing efficient kinase activity. In S. pombe, for example, incomplete DNA synthesis may lead to stabilization of this phosphorylation, preventing mitotic progression.[14] Wee1, conserved among all eukaryotes phosphorylates Tyr15, whereas members of the Cdc25 family are phosphatases, counteracting this activity. The balance between the two is thought to help govern cell cycle progression. Wee1 is controlled upstream by Cdr1, Cdr2, and Pom1.

Cdk1-cyclin complexes are also governed by direct binding of Cdk inhibitor proteins (CKIs). One such protein, already discussed, is Sic1. Sic1 is a stoichiometric inhibitor that binds directly to Clb5,6-Cdk1 complexes. Multisite phosphorylation, by Cdk1-Cln1/2, of Sic1 is thought to time Sic1 ubiquitination and destruction, and by extension, the timing of S-phase entry. Only until Sic1 inhibition is overcome can Clb5,6 activity occur and S phase initiation may begin.

Interactions

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Cdk1 has been shown to interact with:

See also

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Mastl

References

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Further reading

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  • Overview of all the structural information available in the PDB for UniProt: P06493 (Cyclin-dependent kinase 1) at the PDBe-KB.
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