title: Myocardin related transcription factors are required for coordinated cell cycle progression.
abstract: Myocardin related transcription factors A and B (MRTFs) activate serum response factor-driven transcription in response to Rho signaling and changes in actin dynamics. Myocardin and MRTFs have been implicated in anti-proliferative effects on a range of cell types. The precise mechanisms, however, remained elusive. We employed double knockdown of MRTF-A and MRTF-B in NIH 3T3 fibroblasts to evaluate its effects on cell cycle progression and proliferation. We show that transient depletion of MRTFs conveys a modest anti-proliferative effect and impinges on normal cell cycle progression, resulting in significantly shortened G 1 phase and slightly extended S and G 2 phase under normal growth conditions. Under serum-starved conditions we observed aberrant entry into the S and G 2 phases without subsequent cell division. This was accompanied by downregulation of cyclin-CDK inhibitors p27Kip1, p18Ink4c and 19Ink4d as well as upregulation of p21Waf1 and cyclin D1. Extended knockdown led to increased formation of micronuclei, while cells stably depleted of MRTFs tend to become aneuploid and polyploid. Thus, MRTFs are required for accurate cell cycle progression and maintenance of genomic stability in fibroblast cells.
authors: Gene Regulation Lab, Institute for Physiological Chemistry, Medical Faculty, Martin Luther University Halle-Wittenberg; Halle (Saale), Germany.
authors: Dmitry
authors: D
authors: Shaposhnikov
authors: Christian
authors: C
authors: Kuffer
authors: Zuzana
authors: Z
authors: Storchova
authors: Guido
authors: G
authors: Posern
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D002875:Chromosomes / Q000502:physiology; D019938:Cyclin D1 / Q000378:metabolism; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics / Q000378:metabolism; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D051379:Mice; D041681:NIH 3T3 Cells; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D050763:Cyclin-Dependent Kinase Inhibitor p18; D050764:Cyclin-Dependent Kinase Inhibitor p19; D050759:Cyclin-Dependent Kinase Inhibitor p21; C511173:Mrtfa protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014157:Transcription Factors; C503315:myocardin-related transcription factor B, mouse; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: Mrtf; actin; aneuploidy; apoptosis; p27Kip1; transcription
references: Cancer Res. 2010 Jan 15;70(2):501-11
references: 20068148
references: Nature. 1998 Jul 16;394(6690):295-9
references: 9685162
references: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3362-7
references: 18296632
references: Nature. 2004 Mar 11;428(6979):185-9
references: 15014501
references: J Biol Chem. 1999 Dec 31;274(53):38083-90
references: 10608877
references: J Biol Chem. 2003 Oct 17;278(42):41347-54
references: 12902328
references: Nat Rev Mol Cell Biol. 2010 May;11(5):353-65
references: 20414257
references: Cell Cycle. 2012 Jan 1;11(1):141-50
references: 22185759
references: Mol Cell Biol. 1998 Dec;18(12):6962-70
references: 9819384
references: J Cell Sci. 2011 Dec 15;124(Pt 24):4318-31
references: 22223881
references: Mol Cell Biol. 2006 Jun;26(11):4134-48
references: 16705166
references: Proc Natl Acad Sci U S A. 2005 Jun 21;102(25):8916-21
references: 15951419
references: Cell Cycle. 2007 May 15;6(10):1141-6
references: 17495540
references: J Neurosci. 2009 Apr 8;29(14):4512-8
references: 19357276
references: Development. 2010 Jul;137(14):2365-74
references: 20534669
references: J Biol Chem. 2011 Jul 29;286(30):26860-72
references: 21642427
references: J Biol Chem. 2001 Jul 6;276(27):24531-9
references: 11342553
references: Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15122-7
references: 16204380
references: Genes Dev. 2006 Jun 15;20(12):1545-56
references: 16778073
references: Mol Biol Cell. 2007 Oct;18(10):3752-63
references: 17634283
references: Cell. 2008 Feb 8;132(3):487-98
references: 18267078
references: Nat Cell Biol. 2011 Mar;13(3):203-14
references: 21336301
references: Nat Cell Biol. 2009 Mar;11(3):257-68
references: 19198601
references: Curr Opin Cell Biol. 1996 Apr;8(2):205-15
references: 8791420
references: Mol Cell. 2009 Aug 14;35(3):291-304
references: 19683494
references: J Biol Chem. 2004 May 21;279(21):22498-504
references: 15010468
references: Mol Cell Biol. 1996 Mar;16(3):1094-102
references: 8622654
references: Cell. 2003 May 2;113(3):329-42
references: 12732141
references: EMBO J. 2001 Feb 15;20(4):755-66
references: 11179220
references: Cell Cycle. 2007 Dec 15;6(24):3015-20
references: 18075313
references: Nat Cell Biol. 2010 Jul;12(7):711-8
references: 20581838
references: Am J Physiol Cell Physiol. 2007 Jan;292(1):C70-81
references: 16928770
references: J Cell Biochem. 1999 Mar 15;72(4):458-69
references: 10022606
references: Nat Protoc. 2006;1(3):1458-61
references: 17406435
references: Genes Dev. 1995 Apr 15;9(8):935-44
references: 7774811
references: Nat Neurosci. 2010 Sep;13(9):1082-9
references: 20694003
references: Mol Cell Biol. 2005 Apr;25(8):3364-87
references: 15798220
references: Cancer Cell. 2007 Feb;11(2):133-46
references: 17292825
references: Trends Cell Biol. 2006 Nov;16(11):588-96
references: 17035020
references: Mol Cell Biol. 2002 Oct;22(20):7083-92
references: 12242287
references: EMBO J. 2003 May 1;22(9):2036-46
references: 12727871
references: Cell Growth Differ. 1999 Sep;10(9):621-8
references: 10511312
references: J Biol Chem. 2011 Apr 29;286(17):15132-7
references: 21454503