View source for RUNX2

{{Short description|Protein-coding gene in humans}}
{{cs1 config|name-list-style=vanc}}
{{Infobox_gene}}
[[File:Oscillations of Runx2 mRNA levels.png|thumb|Oscillations of Runx2 mRNA levels.<ref name="San Martin_2009" />]]
'''Runt-related transcription factor 2''' (RUNX2) also known as '''core-binding factor subunit alpha-1''' (CBF-alpha-1) is a [[protein]] that in humans is encoded by the ''RUNX2'' [[gene]]. RUNX2 is a key [[transcription factor]] associated with [[osteoblast]] [[cellular differentiation|differentiation]].

It has also been suggested that Runx2 plays a cell proliferation regulatory role in [[cell cycle]] entry and exit in osteoblasts, as well as [[endothelial cells]]. Runx2 suppresses pre-osteoblast proliferation by affecting cell cycle progression in the G1 phase.<ref name="Lucero_2013">{{cite journal | vauthors = Lucero CM, Vega OA, Osorio MM, Tapia JC, Antonelli M, Stein GS, van Wijnen AJ, Galindo MA | title = The cancer-related transcription factor Runx2 modulates cell proliferation in human osteosarcoma cell lines | journal = Journal of Cellular Physiology | volume = 228 | issue = 4 | pages = 714–23 | date = April 2013 | pmid = 22949168 | doi = 10.1002/jcp.24218 | pmc=3593672}}</ref> In osteoblasts, the levels of Runx2 is highest in [[G1 phase|G<sub>1</sub> phase]] and is lowest in [[S phase|S]], [[G2 phase|G<sub>2</sub>]], and [[Mitosis|M]].<ref name="San Martin_2009">{{cite journal | vauthors = San Martin IA, Varela N, Gaete M, Villegas K, Osorio M, Tapia JC, Antonelli M, Mancilla EE, Pereira BP, Nathan SS, Lian JB, Stein JL, Stein GS, van Wijnen AJ, Galindo M | title = Impaired cell cycle regulation of the osteoblast-related heterodimeric transcription factor Runx2-Cbfbeta in osteosarcoma cells | journal = Journal of Cellular Physiology | volume = 221 | issue = 3 | pages = 560–71 | date = December 2009 | pmid = 19739101 | doi = 10.1002/jcp.21894 | pmc=3066433}}</ref> The comprehensive cell cycle regulatory mechanisms that Runx2 may play are still unknown, although it is generally accepted that the varying activity and levels of Runx2 throughout the cell cycle contribute to cell cycle entry and exit, as well as cell cycle progression. These functions are especially important when discussing bone cancer, particularly [[osteosarcoma]] development, that can be attributed to aberrant cell proliferation control.

== Function ==

=== Osteoblast differentiation ===

This protein is a member of the RUNX family of transcription factors and has a [[Runt domain|Runt DNA-binding domain]]. It is essential for osteoblastic differentiation and skeletal [[morphogenesis]]. It acts as a [[Scaffold protein|scaffold]] for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a [[heterodimer]]ic complex. Transcript variants of the gene that encode different protein isoforms result from the use of alternate promoters as well as [[Alternative splicing|alternate splicing]].

The cellular dynamics of Runx2 protein are also important for proper osteoblast differentiation. Runx2 protein is detected in [[preosteoblast]]s and the expression is upregulated in immature osteoblasts and downregulated in mature osteoblasts. It is the first transcription factor required for determination of osteoblast commitment, followed by [[Sp7 transcription factor|Sp7]] and [[Wnt signaling pathway|Wnt-signaling]]. Runx2 is responsible for inducing the differentiation of multipotent [[Mesenchymal stem cell|mesenchymal cells]] into immature osteoblasts, as well as activating expression of several key downstream proteins that maintain osteoblast differentiation and [[bone matrix]] genes.

[[Knockout mouse|Knock-out]] of the DNA-binding activity results in inhibition of osteoblastic differentiation. Because of this, Runx2 is often referred to as the master regulator of bone.<ref name="Wysokinski_2015">{{cite journal | vauthors = Wysokinski D, Pawlowska E, Blasiak J | title = RUNX2: A Master Bone Growth Regulator That May Be Involved in the DNA Damage Response | journal = DNA and Cell Biology | volume = 34 | issue = 5 | pages = 305–15 | date = May 2015 | pmid = 25555110 | doi = 10.1089/dna.2014.2688 }}</ref>

=== Cell cycle regulation ===

In addition to being the master regulator of osteoblast differentiation, Runx2 has also been shown to play several roles in cell cycle regulation. This is due, in part, to the fact that Runx2 interacts with many cellular proliferation genes on a [[Transcription (biology)|transcription]] level, such as [[Myc|c-Myb]] and [[C/EBP]],<ref name="San Martin_2009" /> as well as [[TP53|p53]]/<ref name="Wysokinski_2015" /> These functions are critical for osteoblast proliferation and maintenance. This is often controlled via oscillating levels of Runx2 within throughout cell cycle due to regulated degradation and transcriptional activity.

Oscillating levels of Runx2 within the cell contribute to cell cycle dynamics. In the [[MC3T3-E1]] osteoblast cell line, Runx2 levels are a maximum during G1 and a minimum during G2, S, and mitosis.<ref name="San Martin_2009" /> In addition, the oscillations in Runx2 contribute to G1-related anti-proliferative function.<ref>{{cite journal | vauthors = Galindo M, Pratap J, Young DW, Hovhannisyan H, Im HJ, Choi JY, Lian JB, Stein JL, Stein GS, van Wijnen AJ | title = The bone-specific expression of Runx2 oscillates during the cell cycle to support a G1-related antiproliferative function in osteoblasts | journal = The Journal of Biological Chemistry | volume = 280 | issue = 21 | pages = 20274–85 | date = May 2005 | pmid = 15781466 | doi = 10.1074/jbc.M413665200 | pmc=2895256| doi-access = free }}</ref> It has also been proposed that decreasing levels of Runx2 leads to cell cycle exit for proliferating and differentiating osteoblasts, and that Runx2 plays a role in mediating the final stages of osteoblast via this mechanism.<ref>{{cite journal | vauthors = Pratap J, Galindo M, Zaidi SK, Vradii D, Bhat BM, Robinson JA, Choi JY, Komori T, Stein JL, Lian JB, Stein GS, van Wijnen AJ | title = Cell growth regulatory role of Runx2 during proliferative expansion of preosteoblasts | journal = Cancer Research | volume = 63 | issue = 17 | pages = 5357–62 | date = September 2003 | pmid = 14500368 }}</ref> Current research posits that the levels of Runx2 serve various functions.

In addition, Runx2 has been shown to interact with several [[kinase]]s that contribute to facilitate cell-cycle dependent dynamics via direct protein phosphorylation. Furthermore, Runx2 controls the [[gene expression]] of [[cyclin D2]], [[Cyclin D3|D3]], and the [[P21|CDK inhibitor p21(cip1)]] in hematopoietic cells. It has been shown that on a molecular level, Runx associates with the cdc2 partner [[cyclin B1]] during mitosis.<ref name="Qiao_2006" /> The phosphorylation state of Runx2 also mediates its DNA-binding activity. The Runx2 [[DNA-binding protein|DNA-binding]] activity is correlated with cellular proliferation, which suggests Runx2 phosphorylation may also be related to Runx2-mediated cellular proliferation and cell cycle control. To support this, it has been noted that Runx is phosphorylated at Ser451 by cdc2 kinase, which facilitates cell cycle progression through the regulation of G2 and M phases.<ref name="Qiao_2006">{{cite journal | vauthors = Qiao M, Shapiro P, Fosbrink M, Rus H, Kumar R, Passaniti A | title = Cell cycle-dependent phosphorylation of the RUNX2 transcription factor by cdc2 regulates endothelial cell proliferation | journal = The Journal of Biological Chemistry | volume = 281 | issue = 11 | pages = 7118–28 | date = March 2006 | pmid = 16407259 | doi = 10.1074/jbc.M508162200 | doi-access = free }}</ref>

[[File:Schematic_of_Runx2_Levels_During_Cell_Cycle_Progression.png|thumb|Schematic of Runx2 Levels During Cell Cycle Progression]]

==Pathology==
=== Cleidocranial dysplasia ===

Mutations in Runx2 are associated with the disease [[Cleidocranial dysostosis]]. One study proposes that this phenotype arises partly due to the Runx2 dosage insufficiencies. Because Runx2 promotes exit from the cell cycle, insufficient amounts of Runx2 are related to increased proliferation of osteoblasts observed in patients with cleidocranial disostosis.<ref>{{cite journal | vauthors = Lou Y, Javed A, Hussain S, Colby J, Frederick D, Pratap J, Xie R, Gaur T, van Wijnen AJ, Jones SN, Stein GS, Lian JB, Stein JL | title = A Runx2 threshold for the cleidocranial dysplasia phenotype | journal = Human Molecular Genetics | volume = 18 | issue = 3 | pages = 556–68 | date = February 2009 | pmid = 19028669 | doi = 10.1093/hmg/ddn383 | pmc=2638795}}</ref>

=== Osteosarcoma ===

Variants of Runx2 have been associated with the osteosarcoma phenotype.<ref name="San Martin_2009" /> Current research suggests that this is partly due to the role of Runx2 in mitigating the cell cycle.<ref name="Lucero_2013" /> Runx2 plays a role as a tumor suppressor of osteoblasts by halting cell cycle progression at G<sub>1</sub>.<ref name="San Martin_2009" /> Compared to normal osteoblast cell line MC3T3-E1, the oscillations of Runx2 in osteosarcoma ROS and SaOS cell lines are aberrant when compared to the oscillations of Runx2 levels in normal osteoblasts, suggesting that deregulation of Runx2 levels may contribute to abnormal cell proliferation by an inability to escape the cell cycle. Molecularly, It has been proposed that proteasome inhibition by [[MG132]] can stabilize Runx2 protein levels in late G<sub>1</sub> and S in MC3T3 cells, but not in osteosarcoma cells which consequently leads to a cancerous phenotype.<ref name="Lucero_2013" /><ref name="San Martin_2009" />

==Regulation and co-factors==
Due to its role as a master transcription factor of osteoblast differentiation, the regulation of Runx2 is intricately connected to other processes within the cell.

[[Twist transcription factor|Twist]], [[Msh homeobox 2]] (Msx2), and [[ZBT16|promyeloctic leukemia zinc-finger protein]] (PLZF) act upstream of Runx2. [[Sp7 transcription factor|Osterix (Osx)]] acts downstream of Runx2 and serves as a marker for normal osteoblast differentiation. [[Zinc finger protein 521]] (ZFP521) and [[ATF4|activating transcription factor 4]] (ATF4) are [[Cofactors and coenzymes|cofactors]] of Runx2.<ref>{{Cite journal |doi = 10.1007/bf00348917|pmid = 3627420|title = Large volume full columnar lumbar myelography|journal = Neuroradiology|volume = 29|issue = 4|pages = 371–373|year = 1987|last1 = Jinkins|first1 = J. R.|s2cid = 20760228}}</ref> Binding of the transcriptional coregulator, [[WWTR1|WWTR1 (TAZ)]] to Runx2 promotes transcription.

Furthermore, in proliferating [[chondrocyte]]s, Runx2 is inhibited by [[Cyclin D/Cdk4|CyclinD1/CDK4]] as part of the cell cycle.<ref name="Berti_1997">{{cite journal | vauthors = Berti M, Buso G, Colautti P, Moschini G, Stlevano BM, Tregnaghi C | title = Determination of selenium in blood serum by proton-induced X-ray emission | journal = Analytical Chemistry | volume = 49 | issue = 9 | pages = 1313–5 | date = August 1977 | doi=10.1021/ac50017a008| pmid = 883617 }}</ref>

== Interactions ==

RUNX2 has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[Androgen receptor|AR]]<ref name="pmid19389811">{{cite journal | vauthors = Baniwal SK, Khalid O, Sir D, Buchanan G, Coetzee GA, Frenkel B | title = Repression of Runx2 by androgen receptor (AR) in osteoblasts and prostate cancer cells: AR binds Runx2 and abrogates its recruitment to DNA | journal = Molecular Endocrinology | volume = 23 | issue = 8 | pages = 1203–14 | date = August 2009 | pmid = 19389811 | pmc = 2718746 | doi = 10.1210/me.2008-0470 }}</ref>
* [[Estrogen receptor alpha|ER-α]]<ref name="pmid18755791">{{cite journal | vauthors = Khalid O, Baniwal SK, Purcell DJ, Leclerc N, Gabet Y, Stallcup MR, Coetzee GA, Frenkel B | title = Modulation of Runx2 activity by estrogen receptor-alpha: implications for osteoporosis and breast cancer | journal = Endocrinology | volume = 149 | issue = 12 | pages = 5984–95 | date = December 2008 | pmid = 18755791 | pmc = 2613062 | doi = 10.1210/en.2008-0680 }}</ref>
* [[C-Fos]],<ref name=pmid11274169/><ref name=pmid11641401/>
* [[C-jun]],<ref name="pmid11274169">{{cite journal | vauthors = Hess J, Porte D, Munz C, Angel P | title = AP-1 and Cbfa/runt physically interact and regulate parathyroid hormone-dependent MMP13 expression in osteoblasts through a new osteoblast-specific element 2/AP-1 composite element | journal = The Journal of Biological Chemistry | volume = 276 | issue = 23 | pages = 20029–38 | date = June 2001 | pmid = 11274169 | doi = 10.1074/jbc.M010601200 | doi-access = free }}</ref><ref name="pmid11641401">{{cite journal | vauthors = D'Alonzo RC, Selvamurugan N, Karsenty G, Partridge NC | title = Physical interaction of the activator protein-1 factors c-Fos and c-Jun with Cbfa1 for collagenase-3 promoter activation | journal = The Journal of Biological Chemistry | volume = 277 | issue = 1 | pages = 816–22 | date = January 2002 | pmid = 11641401 | doi = 10.1074/jbc.M107082200 | doi-access = free }}</ref>
* [[HDAC3]],<ref name="pmid15292260">{{cite journal | vauthors = Schroeder TM, Kahler RA, Li X, Westendorf JJ | title = Histone deacetylase 3 interacts with runx2 to repress the osteocalcin promoter and regulate osteoblast differentiation | journal = The Journal of Biological Chemistry | volume = 279 | issue = 40 | pages = 41998–2007 | date = October 2004 | pmid = 15292260 | doi = 10.1074/jbc.M403702200 | doi-access = free }}</ref>
* [[MYST4]],<ref name="pmid11965546">{{cite journal | vauthors = Pelletier N, Champagne N, Stifani S, Yang XJ | title = MOZ and MORF histone acetyltransferases interact with the Runt-domain transcription factor Runx2 | journal = Oncogene | volume = 21 | issue = 17 | pages = 2729–40 | date = April 2002 | pmid = 11965546 | doi = 10.1038/sj.onc.1205367 | doi-access =  }}</ref>
* [[Mothers against decapentaplegic homolog 1|SMAD1]]<ref name=pmid10962029/><ref name=pmid10531362/>
* [[Mothers against decapentaplegic homolog 3|SMAD3]],<ref name="pmid10962029">{{cite journal | vauthors = Zhang YW, Yasui N, Ito K, Huang G, Fujii M, Hanai J, Nogami H, Ochi T, Miyazono K, Ito Y | title = A RUNX2/PEBP2alpha A/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 19 | pages = 10549–54 | date = September 2000 | pmid = 10962029 | pmc = 27062 | doi = 10.1073/pnas.180309597 | bibcode = 2000PNAS...9710549Z | doi-access = free }}</ref><ref name="pmid10531362">{{cite journal | vauthors = Hanai J, Chen LF, Kanno T, Ohtani-Fujita N, Kim WY, Guo WH, Imamura T, Ishidou Y, Fukuchi M, Shi MJ, Stavnezer J, Kawabata M, Miyazono K, Ito Y | title = Interaction and functional cooperation of PEBP2/CBF with Smads. Synergistic induction of the immunoglobulin germline Calpha promoter | journal = The Journal of Biological Chemistry | volume = 274 | issue = 44 | pages = 31577–82 | date = October 1999 | pmid = 10531362 | doi = 10.1074/jbc.274.44.31577 | doi-access = free }}</ref> and
* [[STUB1]].<ref>{{cite journal | vauthors = Li X, Huang M, Zheng H, Wang Y, Ren F, Shang Y, Zhai Y, Irwin DM, Shi Y, Chen D, Chang Z | title = CHIP promotes Runx2 degradation and negatively regulates osteoblast differentiation | journal = The Journal of Cell Biology | volume = 181 | issue = 6 | pages = 959–72 | date = June 2008 | pmid = 18541707 | pmc = 2426947 | doi = 10.1083/jcb.200711044 }}</ref>
and
* [[SMOC1]].<ref>{{cite journal | vauthors = Takahata Y, Hagino H, Kimura A, Urushizaki M, Kobayashi S, Wakamori K, Fujiwara C, Nakamura E, Yu K, Kiyonari H, Bando K, Murakami T, Komori T, Hata K, Nishimura R | title = Smoc1 and Smoc2 regulate bone formation as downstream molecules of Runx2 | journal = Communications Biology | volume = 4 | issue = 1199 | date = October 2021 | page = 1199 | pmid = 34667264 | pmc = 8526618 | doi = 10.1038/s42003-021-02717-7 }}</ref>
{{Div col end}}

[[mir-133 microRNA precursor family|miR-133]] and [[Cyclin D/Cdk4|CyclinD1/CDK4]] directly inhibits Runx2.<ref name="pmid18784367">{{cite journal | vauthors = Li Z, Hassan MQ, Volinia S, van Wijnen AJ, Stein JL, Croce CM, Lian JB, Stein GS | title = A microRNA signature for a BMP2-induced osteoblast lineage commitment program | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 37 | pages = 13906–11 | date = September 2008 | pmid = 18784367 | pmc = 2544552 | doi = 10.1073/pnas.0804438105 | bibcode = 2008PNAS..10513906L | doi-access = free }}</ref><ref name="Berti_1997" />

== See also ==
*[[RUNX1]]
*[[RUNX3]]

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Otto F, Kanegane H, Mundlos S | title = Mutations in the RUNX2 gene in patients with cleidocranial dysplasia | journal = Human Mutation | volume = 19 | issue = 3 | pages = 209–16 | date = March 2002 | pmid = 11857736 | doi = 10.1002/humu.10043 | s2cid = 2578591 | doi-access = free }}
* {{cite journal | vauthors = Komori T | title = [Cbfa1/Runx2, an essential transcription factor for the regulation of osteoblast differentiation] | journal = Nihon Rinsho. Japanese Journal of Clinical Medicine | volume = 60 | pages = 91–7 | date = March 2002 | issue = Suppl 3 | pmid = 11979975 }}
* {{cite journal | vauthors = Stock M, Otto F | title = Control of RUNX2 isoform expression: the role of promoters and enhancers | journal = Journal of Cellular Biochemistry | volume = 95 | issue = 3 | pages = 506–17 | date = June 2005 | pmid = 15838892 | doi = 10.1002/jcb.20471 | s2cid = 29657025 }}
* {{cite journal | vauthors = Blyth K, Cameron ER, Neil JC | title = The RUNX genes: gain or loss of function in cancer | journal = Nature Reviews. Cancer | volume = 5 | issue = 5 | pages = 376–87 | date = May 2005 | pmid = 15864279 | doi = 10.1038/nrc1607 | s2cid = 335980 }}
* {{cite journal | vauthors = Schroeder TM, Jensen ED, Westendorf JJ | title = Runx2: a master organizer of gene transcription in developing and maturing osteoblasts | journal = Birth Defects Research. Part C, Embryo Today | volume = 75 | issue = 3 | pages = 213–25 | date = September 2005 | pmid = 16187316 | doi = 10.1002/bdrc.20043 | doi-access = free }}
* {{cite journal | vauthors = Frenkel B, Hong A, Baniwal SK, Coetzee GA, Ohlsson C, Khalid O, Gabet Y | title = Regulation of adult bone turnover by sex steroids | journal = Journal of Cellular Physiology | volume = 224 | issue = 2 | pages = 305–10 | date = August 2010 | pmid = 20432458 | pmc = 5770230 | doi = 10.1002/jcp.22159 }}
{{refend}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1513/  GeneReviews/NCBI/NIH/UW entry on Cleidocranial Dysplasia]
* {{MeshName|Runx2+protein}}

{{PDB Gallery|geneid=860}}
{{Transcription factors|g4}}

[[Category:Transcription factors]]