Serum response factor explained

Serum response factor, also known as SRF, is a transcription factor protein.^[1]

Function

Serum response factor is a member of the MADS (MCM1, Agamous, Deficiens, and SRF) box superfamily of transcription factors.^[2] This protein binds to the serum response element (SRE) in the promoter region of target genes. This protein regulates the activity of many immediate early genes, for example c-fos, and thereby participates in cell cycle regulation, apoptosis, cell growth, and cell differentiation. This gene is the downstream target of many pathways; for example, the mitogen-activated protein kinase pathway (MAPK) that acts through the ternary complex factors (TCFs).^{[3] [4]}

SRF is important during the development of the embryo, as it has been linked to the formation of mesoderm.^{[5] [6]} In the fully developed mammal, SRF is crucial for the growth of skeletal muscle.^[7] Interaction of SRF with other proteins, such as steroid hormone receptors, may contribute to regulation of muscle growth by steroids.^[8] Interaction of SRF with other proteins such as myocardin or Elk-1 may enhance or suppress expression of genes important for growth of vascular smooth muscle.

Clinical significance

Lack of skin SRF is associated with psoriasis and other skin diseases.^[9]

Interactions

Serum response factor has been shown to interact with:

• ASCC3,^[10]
• ATF6,^[11]
• CEBPB,^{[12] [13]}
• CREB-binding protein,^[14]
• ELK4,^{[11] [15]}
• GATA4,^{[16] [17]}
• GTF2F1,^{[18] [19]}
• GTF2I,^{[20] [21]}
• Myogenin,^{[22] [23]}
• NFYA,^[24]
• Nuclear receptor co-repressor 2,^[25]
• Promyelocytic leukemia protein^[14] and
• Src,^[26] and
• TEAD1.^[27]

See also

• MKL1
• Nuclear actin functions

Further reading

• Esnault C, Stewart A, Gualdrini F, East P, Horswell S, Matthews N, Treisman R . Rho-actin signaling to the MRTF coactivators dominates the immediate transcriptional response to serum in fibroblasts . Genes & Development . 28 . 9 . 943–58 . May 2014 . 24732378 . 4018493 . 10.1101/gad.239327.114 .
• Huh S, Song HR, Jeong GR, Jang H, Seo NH, Lee JH, Lee TH . Suppression of the ERK–SRF axis facilitates somatic cell reprogramming . Experimental & Molecular Medicine . 50 . 2 . e448 . Feb 2018 . 29472703 . 5903827 . 10.1038/emm.2017.279 .
• Pellegrino R, Thavamani A, Calvisi DF, Budczies J, Neumann A, Geffers R, Kroemer J, Greule D, Schirmacher P, Nordheim A, Longerich T . 6 . Serum Response Factor (SRF) Drives the Transcriptional Upregulation of the MDM4 Oncogene in HCC . Cancers . 13 . 2 . January 2021 . 199 . 33429878 . 7829828 . 10.3390/cancers13020199 . free .
• Hu X, Wu Q, Zhang J, Kim J, Chen X, Hartman AA, Eastman AE, Park IH, Guo S . 6 . Reprogramming progressive cells display low CAG promoter activity . Stem Cells . 39 . 1 . 43–54 . January 2021 . 33075202 . 7821215 . 10.1002/stem.3295 .
• Kepser LJ, Khudayberdiev S, Hinojosa LS, Macchi C, Ruscica M, Marcello E, Culmsee C, Grosse R, Rust MB . 6 . Cyclase-associated protein 2 (CAP2) controls MRTF-A localization and SRF activity in mouse embryonic fibroblasts . Scientific Reports . 11 . 1 . 4789 . February 2021 . 33637797 . 7910472 . 10.1038/s41598-021-84213-w . 2021NatSR..11.4789K .

Notes and References

1. Norman C, Runswick M, Pollock R, Treisman R . Isolation and properties of cDNA clones encoding SRF, a transcription factor that binds to the c-fos serum response element . Cell . 55 . 6 . 989–1003 . December 1988 . 3203386 . 10.1016/0092-8674(88)90244-9 . 20004673 .
2. Shore P, Sharrocks AD . The MADS-box family of transcription factors . Eur. J. Biochem. . 229 . 1 . 1–13 . April 1995 . 7744019 . 10.1111/j.1432-1033.1995.0001l.x .
3. Dalton S, Marais R, Wynne J, Treisman R . Isolation and characterization of SRF accessory proteins . Philos. Trans. R. Soc. Lond. B Biol. Sci. . 340 . 1293 . 325–32 . June 1993 . 8103935 . 10.1098/rstb.1993.0074 . 1993RSPTB.340..325D .
4. Web site: SRF serum response factor . Entrez Gene . National Center for Biotechnology Information, National Institutes of Health.
5. Sepulveda JL, Vlahopoulos S, Iyer D, Belaguli N, Schwartz RJ . Combinatorial expression of GATA4, Nkx2-5, and serum response factor directs early cardiac gene activity . J. Biol. Chem. . 277 . 28 . 25775–82 . July 2002 . 11983708 . 10.1074/jbc.M203122200 . free .
6. Barron MR, Belaguli NS, Zhang SX, Trinh M, Iyer D, Merlo X, Lough JW, Parmacek MS, Bruneau BG, Schwartz RJ . Serum response factor, an enriched cardiac mesoderm obligatory factor, is a downstream gene target for Tbx genes . J. Biol. Chem. . 280 . 12 . 11816–28 . March 2005 . 15591049 . 10.1074/jbc.M412408200 . free .
7. Li S, Czubryt MP, McAnally J, Bassel-Duby R, Richardson JA, Wiebel FF, Nordheim A, Olson EN . Requirement for serum response factor for skeletal muscle growth and maturation revealed by tissue-specific gene deletion in mice . Proc. Natl. Acad. Sci. U.S.A. . 102 . 4 . 1082–7 . January 2005 . 15647354 . 545866 . 10.1073/pnas.0409103102 . 2005PNAS..102.1082L . free .
8. Vlahopoulos S, Zimmer WE, Jenster G, Belaguli NS, Balk SP, Brinkmann AO, Lanz RB, Zoumpourlis VC, Schwartz RJ . Recruitment of the androgen receptor via serum response factor facilitates expression of a myogenic gene . J. Biol. Chem. . 280 . 9 . 7786–92 . March 2005 . 15623502 . 10.1074/jbc.M413992200 . free .
9. Koegel H, von Tobel L, Schäfer M, Alberti S, Kremmer E, Mauch C, Hohl D, Wang XJ, Beer HD, Bloch W, Nordheim A, Werner S . Loss of serum response factor in keratinocytes results in hyperproliferative skin disease in mice . J. Clin. Invest. . 119 . 4 . 899–910 . April 2009 . 19307725 . 2662566 . 10.1172/JCI37771 .
10. Jung DJ, Sung HS, Goo YW, Lee HM, Park OK, Jung SY, Lim J, Kim HJ, Lee SK, Kim TS, Lee JW, Lee YC . Novel transcription coactivator complex containing activating signal cointegrator 1 . Mol. Cell. Biol. . 22 . 14 . 5203–11 . July 2002 . 12077347 . 139772 . 10.1128/mcb.22.14.5203-5211.2002.
11. Zhu C, Johansen FE, Prywes R . Interaction of ATF6 and serum response factor . Mol. Cell. Biol. . 17 . 9 . 4957–66 . September 1997 . 9271374 . 232347 . 10.1128/MCB.17.9.4957.
12. Hanlon M, Sealy L . Ras regulates the association of serum response factor and CCAAT/enhancer-binding protein beta . J. Biol. Chem. . 274 . 20 . 14224–8 . May 1999 . 10318842 . 10.1074/jbc.274.20.14224. free .
13. Sealy L, Malone D, Pawlak M . Regulation of the cfos serum response element by C/EBPbeta . Mol. Cell. Biol. . 17 . 3 . 1744–55 . March 1997 . 9032301 . 231899 . 10.1128/mcb.17.3.1744.
14. Matsuzaki K, Minami T, Tojo M, Honda Y, Saitoh N, Nagahiro S, Saya H, Nakao M . PML-nuclear bodies are involved in cellular serum response . Genes Cells . 8 . 3 . 275–86 . March 2003 . 12622724 . 10.1046/j.1365-2443.2003.00632.x. 9697837 . free .
15. Hassler M, Richmond TJ . The B-box dominates SAP-1-SRF interactions in the structure of the ternary complex . EMBO J. . 20 . 12 . 3018–28 . June 2001 . 11406578 . 150215 . 10.1093/emboj/20.12.3018 .
16. Belaguli NS, Sepulveda JL, Nigam V, Charron F, Nemer M, Schwartz RJ . Cardiac tissue enriched factors serum response factor and GATA-4 are mutual coregulators . Mol. Cell. Biol. . 20 . 20 . 7550–8 . October 2000 . 11003651 . 86307 . 10.1128/mcb.20.20.7550-7558.2000.
17. Morin S, Paradis P, Aries A, Nemer M . Serum response factor-GATA ternary complex required for nuclear signaling by a G-protein-coupled receptor . Mol. Cell. Biol. . 21 . 4 . 1036–44 . February 2001 . 11158291 . 99558 . 10.1128/MCB.21.4.1036-1044.2001 .
18. Joliot V, Demma M, Prywes R . Interaction with RAP74 subunit of TFIIF is required for transcriptional activation by serum response factor . Nature . 373 . 6515 . 632–5 . February 1995 . 7854423 . 10.1038/373632a0 . 1995Natur.373..632J . 47196160 .
19. Zhu H, Joliot V, Prywes R . Role of transcription factor TFIIF in serum response factor-activated transcription . J. Biol. Chem. . 269 . 5 . 3489–97 . February 1994 . 10.1016/S0021-9258(17)41889-8 . 8106390 . free .
20. Grueneberg DA, Henry RW, Brauer A, Novina CD, Cheriyath V, Roy AL, Gilman M . A multifunctional DNA-binding protein that promotes the formation of serum response factor/homeodomain complexes: identity to TFII-I . Genes Dev. . 11 . 19 . 2482–93 . October 1997 . 9334314 . 316568 . 10.1101/gad.11.19.2482.
21. Kim DW, Cheriyath V, Roy AL, Cochran BH . TFII-I enhances activation of the c-fos promoter through interactions with upstream elements . Mol. Cell. Biol. . 18 . 6 . 3310–20 . June 1998 . 9584171 . 108912 . 10.1128/mcb.18.6.3310.
22. Groisman R, Masutani H, Leibovitch MP, Robin P, Soudant I, Trouche D, Harel-Bellan A . Physical interaction between the mitogen-responsive serum response factor and myogenic basic-helix-loop-helix proteins . J. Biol. Chem. . 271 . 9 . 5258–64 . March 1996 . 8617811 . 10.1074/jbc.271.9.5258. free .
23. Biesiada E, Hamamori Y, Kedes L, Sartorelli V . Myogenic basic helix-loop-helix proteins and Sp1 interact as components of a multiprotein transcriptional complex required for activity of the human cardiac alpha-actin promoter . Mol. Cell. Biol. . 19 . 4 . 2577–84 . April 1999 . 10082523 . 84050 . 10.1128/MCB.19.4.2577.
24. Yamada K, Osawa H, Granner DK . Identification of proteins that interact with NF-YA . FEBS Lett. . 460 . 1 . 41–5 . October 1999 . 10571058 . 10.1016/s0014-5793(99)01311-3. 28576187 . free .
25. Lee SK, Kim JH, Lee YC, Cheong J, Lee JW . Silencing mediator of retinoic acid and thyroid hormone receptors, as a novel transcriptional corepressor molecule of activating protein-1, nuclear factor-kappaB, and serum response factor . J. Biol. Chem. . 275 . 17 . 12470–4 . April 2000 . 10777532 . 10.1074/jbc.275.17.12470. free .
26. Kim HJ, Kim JH, Lee JW . Steroid receptor coactivator-1 interacts with serum response factor and coactivates serum response element-mediated transactivations . J. Biol. Chem. . 273 . 44 . 28564–7 . October 1998 . 9786846 . 10.1074/jbc.273.44.28564. free .
27. Gupta M, Kogut P, Davis FJ, Belaguli NS, Schwartz RJ, Gupta MP . Physical interaction between the MADS box of serum response factor and the TEA/ATTS DNA-binding domain of transcription enhancer factor-1 . J. Biol. Chem. . 276 . 13 . 10413–22 . March 2001 . 11136726 . 10.1074/jbc.M008625200 . free .