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Gene Review

SRF  -  serum response factor (c-fos serum...

Homo sapiens

Synonyms: MCM1, Serum response factor
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Disease relevance of SRF


Psychiatry related information on SRF

  • Thus, SRF-MYOCD overexpression in small cerebral arteries appears to initiate independently of Abeta a pathogenic pathway mediating arterial hypercontractility and CBF dysregulation, which are associated with Alzheimer's dementia [6].
  • In contrast, Id, a natural inhibitor of myogenic bHLH proteins, did not bind SRF in any of the situations tested [7].
  • A role in learning for SRF: deletion in the adult forebrain disrupts LTD and the formation of an immediate memory of a novel context [8].
  • Based on these results, we have proposed that blockade of SRF may underlie the action of phenytoin, carbamazepine, phenobarbital, valproic acid, and benzodiazepines against generalized tonic-clonic seizures in humans and maximal electroshock seizures in animals [9].

High impact information on SRF

  • One of the most exciting recent discoveries was the identification of the serum response factor (SRF) coactivator gene myocardin that appears to be required for expression of many SMC differentiation marker genes, and for initial differentiation of SMC during development [10].
  • Hop encodes an unusual homeodomain protein that modulates SRF-dependent cardiac-specific gene expression and cardiac development [11].
  • 5. HOP does not bind DNA and acts as an antagonist of serum response factor (SRF), which regulates the opposing processes of proliferation and myogenesis [12].
  • We propose that HOP modulates SRF activity during heart development; its absence results in an imbalance between cardiomyocyte proliferation and differentiation with consequent abnormalities in cardiac morphogenesis [12].
  • Myocardin belongs to the SAP domain family of nuclear proteins and activates cardiac muscle promoters by associating with SRF [13].

Chemical compound and disease context of SRF


Biological context of SRF


Anatomical context of SRF


Associations of SRF with chemical compounds

  • However, calcineurin inhibitors and the tyrosine kinase inhibitor genistein selectively suppressed SRF activation by M1, but not by Galpha(13)QL, indicating the presence of separate pathways [20].
  • Steroid receptor coactivator-1 (SRC-1) specifically bound to serum response factor (SRF), as demonstrated by glutathione S-transferase pull down assays, and the yeast and mammalian two-hybrid tests [18].
  • Substitution of this target lysine for alanine did not affect the translocation of SRF to PML-nuclear bodies [23].
  • Western blotting analysis showed that the expressions of the ERalpha and SRF protein decreased significantly with genistein treatment (P<0.05) [24].
  • The ribosomal S6 kinase pp90rsk, a growth factor-inducible kinase, phosphorylates SRF in vitro at serine 103, the site that becomes newly phosphorylated upon growth factor stimulation in vivo [25].

Physical interactions of SRF


Enzymatic interactions of SRF

  • Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro [29].
  • All the glycosylation sites identified in SRF are situated in a relatively short region of the primary sequence close to or within the transcriptional activation domain which is distant from the major sites of phosphorylation catalyzed by casein kinase II [30].

Regulatory relationships of SRF

  • HERP1 inhibits myocardin-induced vascular smooth muscle cell differentiation by interfering with SRF binding to CArG box [22].
  • These results suggest that neuronal MKL1 contributes to SRF-regulated gene expression induced by BDNF or synaptic activity [31].
  • Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1 [32].
  • Mutant forms of p116Rip that fail to oligomerize or bind to MBS are still capable of inhibiting SRF activity [33].
  • SAP-1 and Elk-1 are members of a large group of eukaryotic transcription factors that contain a conserved ETS DNA binding domain and that cooperate with the serum response factor (SRF) to activate transcription of the c-fos protooncogene [34].

Other interactions of SRF


Analytical, diagnostic and therapeutic context of SRF

  • Using real time RT-PCR, we have shown that HSP and SRF mRNA were both regulated by genistein in a time- and dose-dependent manner; however, it appears that only the effect of genistein on SRF mRNA, but not HSP mRNA expression, can be partially abolished by cotreatment with estrogen antagonist ICI 182,780 [24].
  • Here, we report the identification, purification, and molecular cloning of a human protein that promotes the formation of stable higher-order complexes of SRF and Phox1 [36].
  • Direct, competition, and supershift electrophoretic mobility shift assays revealed highly enriched specific binding activity at the betaA/T-rich element that was antigenically distinct from GATA-4, MEF2A-D, SRF, and Oct-1, nuclear proteins that were previously shown to bind A/T-rich elements [37].
  • Strikingly, in both the mammalian two-hybrid assay and in vivo coimmunoprecipitations, the association of SRF and p35-C/EBPbeta but not p20-C/EBPbeta is dramatically stimulated by activated Ras [38].
  • TIMP-3 inhibition was further confirmed by reverse transcriptase/polymerase chain reaction, immunoblotting, and immunostaining of human lung fibroblasts transfected with SRF fused to DsRed2 (a red variant of green fluorescent protein) [5].


  1. Serum response factor is a critical requirement for VEGF signaling in endothelial cells and VEGF-induced angiogenesis. Chai, J., Jones, M.K., Tarnawski, A.S. FASEB J. (2004) [Pubmed]
  2. Identification of multiple SRF N-terminal phosphorylation sites affecting DNA binding properties. Janknecht, R., Hipskind, R.A., Houthaeve, T., Nordheim, A., Stunnenberg, H.G. EMBO J. (1992) [Pubmed]
  3. Casein kinase II phosphorylation increases the rate of serum response factor-binding site exchange. Marais, R.M., Hsuan, J.J., McGuigan, C., Wynne, J., Treisman, R. EMBO J. (1992) [Pubmed]
  4. Immediate-early gene induction by the stresses anisomycin and arsenite in human osteosarcoma cells involves MAPK cascade signaling to Elk-1, CREB and SRF. Bébien, M., Salinas, S., Becamel, C., Richard, V., Linares, L., Hipskind, R.A. Oncogene (2003) [Pubmed]
  5. Tissue inhibitor of metalloproteinase-3 downregulation in lymphangioleiomyomatosis: potential consequence of abnormal serum response factor expression. Zhe, X., Yang, Y., Jakkaraju, S., Schuger, L. Am. J. Respir. Cell Mol. Biol. (2003) [Pubmed]
  6. Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype. Chow, N., Bell, R.D., Deane, R., Streb, J.W., Chen, J., Brooks, A., Van Nostrand, W., Miano, J.M., Zlokovic, B.V. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  7. Physical interaction between the mitogen-responsive serum response factor and myogenic basic-helix-loop-helix proteins. Groisman, R., Masutani, H., Leibovitch, M.P., Robin, P., Soudant, I., Trouche, D., Harel-Bellan, A. J. Biol. Chem. (1996) [Pubmed]
  8. A role in learning for SRF: deletion in the adult forebrain disrupts LTD and the formation of an immediate memory of a novel context. Etkin, A., Alarcón, J.M., Weisberg, S.P., Touzani, K., Huang, Y.Y., Nordheim, A., Kandel, E.R. Neuron (2006) [Pubmed]
  9. Anticonvulsant drugs: mechanisms of action. Macdonald, R.L., McLean, M.J. Advances in neurology. (1986) [Pubmed]
  10. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Owens, G.K., Kumar, M.S., Wamhoff, B.R. Physiol. Rev. (2004) [Pubmed]
  11. Hop is an unusual homeobox gene that modulates cardiac development. Chen, F., Kook, H., Milewski, R., Gitler, A.D., Lu, M.M., Li, J., Nazarian, R., Schnepp, R., Jen, K., Biben, C., Runke, G., Mackay, J.P., Novotny, J., Schwartz, R.J., Harvey, R.P., Mullins, M.C., Epstein, J.A. Cell (2002) [Pubmed]
  12. Modulation of cardiac growth and development by HOP, an unusual homeodomain protein. Shin, C.H., Liu, Z.P., Passier, R., Zhang, C.L., Wang, D.Z., Harris, T.M., Yamagishi, H., Richardson, J.A., Childs, G., Olson, E.N. Cell (2002) [Pubmed]
  13. Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Wang, D., Chang, P.S., Wang, Z., Sutherland, L., Richardson, J.A., Small, E., Krieg, P.A., Olson, E.N. Cell (2001) [Pubmed]
  15. Myocardin induces cardiomyocyte hypertrophy. Xing, W., Zhang, T.C., Cao, D., Wang, Z., Antos, C.L., Li, S., Wang, Y., Olson, E.N., Wang, D.Z. Circ. Res. (2006) [Pubmed]
  16. Antiepileptic drug actions. Macdonald, R.L. Epilepsia (1989) [Pubmed]
  17. Serum response factor binding sites differ in three human cell types. Cooper, S.J., Trinklein, N.D., Nguyen, L., Myers, R.M. Genome Res. (2007) [Pubmed]
  18. Steroid receptor coactivator-1 interacts with serum response factor and coactivates serum response element-mediated transactivations. Kim, H.J., Kim, J.H., Lee, J.W. J. Biol. Chem. (1998) [Pubmed]
  19. Megakaryoblastic leukemia factor-1 transduces cytoskeletal signals and induces smooth muscle cell differentiation from undifferentiated embryonic stem cells. Du, K.L., Chen, M., Li, J., Lepore, J.J., Mericko, P., Parmacek, M.S. J. Biol. Chem. (2004) [Pubmed]
  20. Serum response factor activation by muscarinic receptors via RhoA. Novel pathway specific to M1 subtype involving calmodulin, calcineurin, and Pyk2. Lin, K., Wang, D., Sadée, W. J. Biol. Chem. (2002) [Pubmed]
  21. Megakaryoblastic leukemia-1/2, a transcriptional co-activator of serum response factor, is required for skeletal myogenic differentiation. Selvaraj, A., Prywes, R. J. Biol. Chem. (2003) [Pubmed]
  22. HERP1 inhibits myocardin-induced vascular smooth muscle cell differentiation by interfering with SRF binding to CArG box. Doi, H., Iso, T., Yamazaki, M., Akiyama, H., Kanai, H., Sato, H., Kawai-Kowase, K., Tanaka, T., Maeno, T., Okamoto, E., Arai, M., Kedes, L., Kurabayashi, M. Arterioscler. Thromb. Vasc. Biol. (2005) [Pubmed]
  23. Serum response factor is modulated by the SUMO-1 conjugation system. Matsuzaki, K., Minami, T., Tojo, M., Honda, Y., Uchimura, Y., Saitoh, H., Yasuda, H., Nagahiro, S., Saya, H., Nakao, M. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  24. Inhibitory actions of genistein in human breast cancer (MCF-7) cells. Chen, W.F., Huang, M.H., Tzang, C.H., Yang, M., Wong, M.S. Biochim. Biophys. Acta (2003) [Pubmed]
  25. A growth factor-induced kinase phosphorylates the serum response factor at a site that regulates its DNA-binding activity. Rivera, V.M., Miranti, C.K., Misra, R.P., Ginty, D.D., Chen, R.H., Blenis, J., Greenberg, M.E. Mol. Cell. Biol. (1993) [Pubmed]
  26. PML-nuclear bodies are involved in cellular serum response. Matsuzaki, K., Minami, T., Tojo, M., Honda, Y., Saitoh, N., Nagahiro, S., Saya, H., Nakao, M. Genes Cells (2003) [Pubmed]
  27. Interaction with RAP74 subunit of TFIIF is required for transcriptional activation by serum response factor. Joliot, V., Demma, M., Prywes, R. Nature (1995) [Pubmed]
  28. Interaction of ATF6 and serum response factor. Zhu, C., Johansen, F.E., Prywes, R. Mol. Cell. Biol. (1997) [Pubmed]
  29. Mutation of serum response factor phosphorylation sites and the mechanism by which its DNA-binding activity is increased by casein kinase II. Manak, J.R., Prywes, R. Mol. Cell. Biol. (1991) [Pubmed]
  30. Localization of O-GlcNAc modification on the serum response transcription factor. Reason, A.J., Morris, H.R., Panico, M., Marais, R., Treisman, R.H., Haltiwanger, R.S., Hart, G.W., Kelly, W.G., Dell, A. J. Biol. Chem. (1992) [Pubmed]
  31. Role of megakaryoblastic acute leukemia-1 in ERK1/2-dependent stimulation of serum response factor-driven transcription by BDNF or increased synaptic activity. Kalita, K., Kharebava, G., Zheng, J.J., Hetman, M. J. Neurosci. (2006) [Pubmed]
  32. Imbalanced plasminogen system in lymphangioleiomyomatosis: potential role of serum response factor. Zhe, X., Yang, Y., Schuger, L. Am. J. Respir. Cell Mol. Biol. (2005) [Pubmed]
  33. Inhibition of RhoA-mediated SRF activation by p116Rip. Mulder, J., Ariaens, A., van Horck, F.P., Moolenaar, W.H. FEBS Lett. (2005) [Pubmed]
  34. Structure of the elk-1-DNA complex reveals how DNA-distal residues affect ETS domain recognition of DNA. Mo, Y., Vaessen, B., Johnston, K., Marmorstein, R. Nat. Struct. Biol. (2000) [Pubmed]
  35. Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes. Cen, B., Selvaraj, A., Burgess, R.C., Hitzler, J.K., Ma, Z., Morris, S.W., Prywes, R. Mol. Cell. Biol. (2003) [Pubmed]
  36. A multifunctional DNA-binding protein that promotes the formation of serum response factor/homeodomain complexes: identity to TFII-I. Grueneberg, D.A., Henry, R.W., Brauer, A., Novina, C.D., Cheriyath, V., Roy, A.L., Gilman, M. Genes Dev. (1997) [Pubmed]
  37. Nuclear protein binding at the beta-myosin heavy chain A/T-rich element is enriched following increased skeletal muscle activity. Vyas, D.R., McCarthy, J.J., Tsika, R.W. J. Biol. Chem. (1999) [Pubmed]
  38. Ras regulates the association of serum response factor and CCAAT/enhancer-binding protein beta. Hanlon, M., Sealy, L. J. Biol. Chem. (1999) [Pubmed]
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