RUNX2

Last updated
RUNX2
Protein RUNX2 PDB 1cmo.png
Identifiers
Aliases RUNX2 , AML3, CBF-alpha-1, CBFA1, CCD, CCD1, CLCD, OSF-2, OSF2, PEA2aA, PEBP2aA, runt related transcription factor 2, Runx2 mRNA, RUNX family transcription factor 2
External IDs OMIM: 600211 MGI: 99829 HomoloGene: 68389 GeneCards: RUNX2
Orthologs
SpeciesHumanMouse
Entrez

860

12393

Ensembl

ENSG00000124813

ENSMUSG00000039153

UniProt

Q13950

Q08775

RefSeq (mRNA)

NM_001015051
NM_001024630
NM_001278478
NM_004348
NM_001369405

Contents

RefSeq (protein)

NP_001015051
NP_001019801
NP_001265407
NP_001356334

Location (UCSC) Chr 6: 45.33 – 45.66 Mb Chr 17: 44.81 – 45.13 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Oscillations of Runx2 mRNA levels. Oscillations of Runx2 mRNA levels.png
Oscillations of Runx2 mRNA levels.

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 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. [6] In osteoblasts, the levels of Runx2 is highest in G1 phase and is lowest in S, G2, and M. [5] 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 DNA-binding domain. It is essential for osteoblastic differentiation and skeletal morphogenesis. It acts as a 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 heterodimeric complex. Transcript variants of the gene that encode different protein isoforms result from the use of alternate promoters as well as alternate splicing.

The cellular dynamics of Runx2 protein are also important for proper osteoblast differentiation. Runx2 protein is detected in preosteoblasts 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 and Wnt-signaling. Runx2 is responsible for inducing the differentiation of multipotent mesenchymal cells into immature osteoblasts, as well as activating expression of several key downstream proteins that maintain osteoblast differentiation and bone matrix genes.

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. [7]

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 level, such as c-Myb and C/EBP, [5] as well as p53/ [7] 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. [5] In addition, the oscillations in Runx2 contribute to G1-related anti-proliferative function. [8] 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. [9] Current research posits that the levels of Runx2 serve various functions.

In addition, Runx2 has been shown to interact with several kinases that contribute to facilitate cell-cycle dependent dynamics via direct protein phosphorylation. Furthermore, Runx2 controls the gene expression of cyclin D2, D3, and the 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. [10] The phosphorylation state of Runx2 also mediates its DNA-binding activity. The Runx2 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. [10]

Schematic of Runx2 Levels During Cell Cycle Progression Schematic of Runx2 Levels During Cell Cycle Progression.png
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. [11]

Osteosarcoma

Variants of Runx2 have been associated with the osteosarcoma phenotype. [5] Current research suggests that this is partly due to the role of Runx2 in mitigating the cell cycle. [6] Runx2 plays a role as a tumor suppressor of osteoblasts by halting cell cycle progression at G1. [5] 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 G1 and S in MC3T3 cells, but not in osteosarcoma cells which consequently leads to a cancerous phenotype. [6] [5]

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, Msh homeobox 2 (Msx2), and promyeloctic leukemia zinc-finger protein (PLZF) act upstream of Runx2. Osterix (Osx) acts downstream of Runx2 and serves as a marker for normal osteoblast differentiation. Zinc finger protein 521 (ZFP521) and activating transcription factor 4 (ATF4) are cofactors of Runx2. [12] Binding of the transcriptional coregulator, WWTR1 (TAZ) to Runx2 promotes transcription.

Furthermore, in proliferating chondrocytes, Runx2 is inhibited by CyclinD1/CDK4 as part of the cell cycle. [13]

Interactions

RUNX2 has been shown to interact with:

and

miR-133 and CyclinD1/CDK4 directly inhibits Runx2. [24] [13]

See also

Related Research Articles

E2F is a group of genes that encodes a family of transcription factors (TF) in higher eukaryotes. Three of them are activators: E2F1, 2 and E2F3a. Six others act as suppressors: E2F3b, E2F4-8. All of them are involved in the cell cycle regulation and synthesis of DNA in mammalian cells. E2Fs as TFs bind to the TTTCCCGC consensus binding site in the target promoter sequence.

<span class="mw-page-title-main">Transcription factor Sp1</span> Protein-coding gene in the species Homo sapiens

Transcription factor Sp1, also known as specificity protein 1* is a protein that in humans is encoded by the SP1 gene.

<span class="mw-page-title-main">Protein c-Fos</span> Mammalian protein found in Homo sapiens

Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the FOS gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV. It is a part of a bigger Fos family of transcription factors which includes c-Fos, FosB, Fra-1 and Fra-2. It has been mapped to chromosome region 14q21→q31. c-Fos encodes a 62 kDa protein, which forms heterodimer with c-jun, resulting in the formation of AP-1 complex which binds DNA at AP-1 specific sites at the promoter and enhancer regions of target genes and converts extracellular signals into changes of gene expression. It plays an important role in many cellular functions and has been found to be overexpressed in a variety of cancers.

<span class="mw-page-title-main">Transcription factor Jun</span> Mammalian protein found in Homo sapiens

Transcription factor Jun is a protein that in humans is encoded by the JUN gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only later rediscovered as the product of the JUN gene. c-jun was the first oncogenic transcription factor discovered. The proto-oncogene c-Jun is the cellular homolog of the viral oncoprotein v-jun. The viral homolog v-jun was discovered in avian sarcoma virus 17 and was named for ju-nana, the Japanese word for 17. The human JUN encodes a protein that is highly similar to the viral protein, which interacts directly with specific target DNA sequences to regulate gene expression. This gene is intronless and is mapped to 1p32-p31, a chromosomal region involved in both translocations and deletions in human malignancies.

<span class="mw-page-title-main">AP-1 transcription factor</span> Instance of defined set in Homo sapiens with Reactome ID (R-HSA-6806560)

Activator protein 1 (AP-1) is a transcription factor that regulates gene expression in response to a variety of stimuli, including cytokines, growth factors, stress, and bacterial and viral infections. AP-1 controls a number of cellular processes including differentiation, proliferation, and apoptosis. The structure of AP-1 is a heterodimer composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families.

mir-133 microRNA precursor family

mir-133 is a type of non-coding RNA called a microRNA that was first experimentally characterised in mice. Homologues have since been discovered in several other species including invertebrates such as the fruitfly Drosophila melanogaster. Each species often encodes multiple microRNAs with identical or similar mature sequence. For example, in the human genome there are three known miR-133 genes: miR-133a-1, miR-133a-2 and miR-133b found on chromosomes 18, 20 and 6 respectively. The mature sequence is excised from the 3' arm of the hairpin. miR-133 is expressed in muscle tissue and appears to repress the expression of non-muscle genes.

<span class="mw-page-title-main">Cyclin D1</span> Protein found in humans

Cyclin D1 is a protein that in humans is encoded by the CCND1 gene.

<span class="mw-page-title-main">RUNX1</span> Protein-coding gene in humans

Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2) is a protein that in humans is encoded by the RUNX1 gene.

<span class="mw-page-title-main">CHUK</span> Protein-coding gene in humans

Inhibitor of nuclear factor kappa-B kinase subunit alpha (IKK-α) also known as IKK1 or conserved helix-loop-helix ubiquitous kinase (CHUK) is a protein kinase that in humans is encoded by the CHUK gene. IKK-α is part of the IκB kinase complex that plays an important role in regulating the NF-κB transcription factor. However, IKK-α has many additional cellular targets, and is thought to function independently of the NF-κB pathway to regulate epidermal differentiation.

<span class="mw-page-title-main">Cyclin D2</span> Protein-coding gene in humans

G1/S-specific cyclin-D2 is a protein that in humans is encoded by the CCND2 gene.

<span class="mw-page-title-main">MYBL2</span> Protein-coding gene in the species Homo sapiens

Myb-related protein B is a protein that in humans is encoded by the MYBL2 gene.

<span class="mw-page-title-main">ATF4</span> Mammalian protein found in Homo sapiens

Activating transcription factor 4 , also known as ATF4, is a protein that in humans is encoded by the ATF4 gene.

<span class="mw-page-title-main">KLF4</span> Protein-coding gene in the species Homo sapiens

Kruppel-like factor 4 is a member of the KLF family of zinc finger transcription factors, which belongs to the relatively large family of SP1-like transcription factors. KLF4 is involved in the regulation of proliferation, differentiation, apoptosis and somatic cell reprogramming. Evidence also suggests that KLF4 is a tumor suppressor in certain cancers, including colorectal cancer. It has three C2H2-zinc fingers at its carboxyl terminus that are closely related to another KLF, KLF2. It has two nuclear localization sequences that signals it to localize to the nucleus. In embryonic stem cells (ESCs), KLF4 has been demonstrated to be a good indicator of stem-like capacity. It is suggested that the same is true in mesenchymal stem cells (MSCs).

<span class="mw-page-title-main">E2F3</span> Protein-coding gene in the species Homo sapiens

Transcription factor E2F3 is a protein that in humans is encoded by the E2F3 gene.

<span class="mw-page-title-main">IRF2</span> Protein-coding gene in the species Homo sapiens

Interferon regulatory factor 2 is a protein that in humans is encoded by the IRF2 gene.

<span class="mw-page-title-main">SIM2</span> Protein-coding gene in the species Homo sapiens

Single-minded homolog 2 is a protein that in humans is encoded by the SIM2 gene. It plays a major role in the development of the central nervous system midline as well as the construction of the face and head.

<span class="mw-page-title-main">KDM5A</span> Protein-coding gene in the species Homo sapiens

Lysine-specific demethylase 5A is an enzyme that in humans is encoded by the KDM5A gene.

<span class="mw-page-title-main">MIZF</span> Protein-coding gene in the species Homo sapiens

Histone H4 transcription factor is a protein that in humans is encoded by the HINFP gene.

<span class="mw-page-title-main">Sp7 transcription factor</span> Protein-coding gene in the species Homo sapiens

Transcription factor Sp7, also called osterix (Osx), is a protein that in humans is encoded by the SP7 gene. It is a member of the Sp family of zinc-finger transcription factors It is highly conserved among bone-forming vertebrate species It plays a major role, along with Runx2 and Dlx5 in driving the differentiation of mesenchymal precursor cells into osteoblasts and eventually osteocytes. Sp7 also plays a regulatory role by inhibiting chondrocyte differentiation maintaining the balance between differentiation of mesenchymal precursor cells into ossified bone or cartilage. Mutations of this gene have been associated with multiple dysfunctional bone phenotypes in vertebrates. During development, a mouse embryo model with Sp7 expression knocked out had no formation of bone tissue. Through the use of GWAS studies, the Sp7 locus in humans has been strongly associated with bone mass density. In addition there is significant genetic evidence for its role in diseases such as Osteogenesis imperfecta (OI).

<span class="mw-page-title-main">Retinoblastoma protein</span> Mammalian protein found in Homo sapiens

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References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000124813 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000039153 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 4 5 6 7 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 (December 2009). "Impaired cell cycle regulation of the osteoblast-related heterodimeric transcription factor Runx2-Cbfbeta in osteosarcoma cells". Journal of Cellular Physiology. 221 (3): 560–71. doi:10.1002/jcp.21894. PMC   3066433 . PMID   19739101.
  6. 1 2 3 Lucero CM, Vega OA, Osorio MM, Tapia JC, Antonelli M, Stein GS, van Wijnen AJ, Galindo MA (April 2013). "The cancer-related transcription factor Runx2 modulates cell proliferation in human osteosarcoma cell lines". Journal of Cellular Physiology. 228 (4): 714–23. doi:10.1002/jcp.24218. PMC   3593672 . PMID   22949168.
  7. 1 2 Wysokinski D, Pawlowska E, Blasiak J (May 2015). "RUNX2: A Master Bone Growth Regulator That May Be Involved in the DNA Damage Response". DNA and Cell Biology. 34 (5): 305–15. doi:10.1089/dna.2014.2688. PMID   25555110.
  8. ↑ Galindo M, Pratap J, Young DW, Hovhannisyan H, Im HJ, Choi JY, Lian JB, Stein JL, Stein GS, van Wijnen AJ (May 2005). "The bone-specific expression of Runx2 oscillates during the cell cycle to support a G1-related antiproliferative function in osteoblasts". The Journal of Biological Chemistry. 280 (21): 20274–85. doi: 10.1074/jbc.M413665200 . PMC   2895256 . PMID   15781466.
  9. ↑ 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 (September 2003). "Cell growth regulatory role of Runx2 during proliferative expansion of preosteoblasts". Cancer Research. 63 (17): 5357–62. PMID   14500368.
  10. 1 2 Qiao M, Shapiro P, Fosbrink M, Rus H, Kumar R, Passaniti A (March 2006). "Cell cycle-dependent phosphorylation of the RUNX2 transcription factor by cdc2 regulates endothelial cell proliferation". The Journal of Biological Chemistry. 281 (11): 7118–28. doi: 10.1074/jbc.M508162200 . PMID   16407259.
  11. ↑ 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 (February 2009). "A Runx2 threshold for the cleidocranial dysplasia phenotype". Human Molecular Genetics. 18 (3): 556–68. doi:10.1093/hmg/ddn383. PMC   2638795 . PMID   19028669.
  12. ↑ Jinkins JR (1987). "Large volume full columnar lumbar myelography". Neuroradiology. 29 (4): 371–373. doi:10.1007/bf00348917. PMID   3627420. S2CID   20760228.
  13. 1 2 Berti M, Buso G, Colautti P, Moschini G, Stlevano BM, Tregnaghi C (August 1977). "Determination of selenium in blood serum by proton-induced X-ray emission". Analytical Chemistry. 49 (9): 1313–5. doi:10.1021/ac50017a008. PMID   883617.
  14. ↑ Baniwal SK, Khalid O, Sir D, Buchanan G, Coetzee GA, Frenkel B (August 2009). "Repression of Runx2 by androgen receptor (AR) in osteoblasts and prostate cancer cells: AR binds Runx2 and abrogates its recruitment to DNA". Molecular Endocrinology. 23 (8): 1203–14. doi:10.1210/me.2008-0470. PMC   2718746 . PMID   19389811.
  15. ↑ Khalid O, Baniwal SK, Purcell DJ, Leclerc N, Gabet Y, Stallcup MR, Coetzee GA, Frenkel B (December 2008). "Modulation of Runx2 activity by estrogen receptor-alpha: implications for osteoporosis and breast cancer". Endocrinology. 149 (12): 5984–95. doi:10.1210/en.2008-0680. PMC   2613062 . PMID   18755791.
  16. 1 2 Hess J, Porte D, Munz C, Angel P (June 2001). "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". The Journal of Biological Chemistry. 276 (23): 20029–38. doi: 10.1074/jbc.M010601200 . PMID   11274169.
  17. 1 2 D'Alonzo RC, Selvamurugan N, Karsenty G, Partridge NC (January 2002). "Physical interaction of the activator protein-1 factors c-Fos and c-Jun with Cbfa1 for collagenase-3 promoter activation". The Journal of Biological Chemistry. 277 (1): 816–22. doi: 10.1074/jbc.M107082200 . PMID   11641401.
  18. ↑ Schroeder TM, Kahler RA, Li X, Westendorf JJ (October 2004). "Histone deacetylase 3 interacts with runx2 to repress the osteocalcin promoter and regulate osteoblast differentiation". The Journal of Biological Chemistry. 279 (40): 41998–2007. doi: 10.1074/jbc.M403702200 . PMID   15292260.
  19. ↑ Pelletier N, Champagne N, Stifani S, Yang XJ (April 2002). "MOZ and MORF histone acetyltransferases interact with the Runt-domain transcription factor Runx2". Oncogene. 21 (17): 2729–40. doi:10.1038/sj.onc.1205367. PMID   11965546.
  20. 1 2 Zhang YW, Yasui N, Ito K, Huang G, Fujii M, Hanai J, Nogami H, Ochi T, Miyazono K, Ito Y (September 2000). "A RUNX2/PEBP2alpha A/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia". Proceedings of the National Academy of Sciences of the United States of America. 97 (19): 10549–54. Bibcode:2000PNAS...9710549Z. doi: 10.1073/pnas.180309597 . PMC   27062 . PMID   10962029.
  21. 1 2 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 (October 1999). "Interaction and functional cooperation of PEBP2/CBF with Smads. Synergistic induction of the immunoglobulin germline Calpha promoter". The Journal of Biological Chemistry. 274 (44): 31577–82. doi: 10.1074/jbc.274.44.31577 . PMID   10531362.
  22. ↑ Li X, Huang M, Zheng H, Wang Y, Ren F, Shang Y, Zhai Y, Irwin DM, Shi Y, Chen D, Chang Z (June 2008). "CHIP promotes Runx2 degradation and negatively regulates osteoblast differentiation". The Journal of Cell Biology. 181 (6): 959–72. doi:10.1083/jcb.200711044. PMC   2426947 . PMID   18541707.
  23. ↑ 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 (October 2021). "Smoc1 and Smoc2 regulate bone formation as downstream molecules of Runx2". Communications Biology. 4 (1199): 1199. doi:10.1038/s42003-021-02717-7. PMC   8526618 . PMID   34667264.
  24. ↑ Li Z, Hassan MQ, Volinia S, van Wijnen AJ, Stein JL, Croce CM, Lian JB, Stein GS (September 2008). "A microRNA signature for a BMP2-induced osteoblast lineage commitment program". Proceedings of the National Academy of Sciences of the United States of America. 105 (37): 13906–11. Bibcode:2008PNAS..10513906L. doi: 10.1073/pnas.0804438105 . PMC   2544552 . PMID   18784367.

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