A transcriptional cross-talk between RhoA and c-Myc inhibits the RhoA/Rock-dependent cytoskeleton.
The GTPase RhoA participates in a number of cellular processes, including cytoskeletal organization, mitogenesis and tumorigenesis. We have previously shown that the transforming activity of an oncogenic version of RhoA (Q63L mutant) was highly dependent on the transcriptional factor c-Myc. In contrast to these positive effects in the RhoA route, we show here that c-Myc affects negatively the F-actin cytoskeleton induced by RhoA(Q63L) and its downstream effector, the serine/threonine kinase Rock. This effect entails the activation of a transcriptional program that requires synergistic interactions with RhoA-derived signals and that includes the upregulation of the GTPase Cdc42 and its downstream element Pak1 as well as the repression of specific integrin subunits. The negative effects of c-Myc in the F-actin cytoskeleton are eliminated by the establishment of cell-to-cell contacts, an effect associated with the rescue of Pak1 and integrin levels at the post-transcriptional and transcriptional levels, respectively. These results reveal the presence of a hitherto unknown signaling feed-back loop between RhoA and c--Myc oncogenes that can contribute to maintain fluid cytoskeletal dynamics in cancer cells.
Sauzeau
V
V
Centro de Investigación del Cáncer, CSIC-University of Salamanca, Campus Unamuno, Salamanca, Spain.
Berenjeno
I M
IM
Citterio
C
C
Bustelo
X R
XR
D000818:Animals; D003599:Cytoskeleton / Q000378:metabolism*; D022001:Focal Adhesions; D051379:Mice; D041681:NIH 3T3 Cells; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D014158:Transcription, Genetic; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D016271:Proto-Oncogene Proteins c-myc; D020742:rhoA GTP-Binding Protein
J Biol Chem. 1996 Aug 23;271(34):20246-9
8702756
Nature. 2002 Dec 12;420(6916):629-35
12478284
Oncogene. 2004 Jul 22;23(33):5577-85
15122327
Curr Biol. 1997 Oct 1;7(10):794-7
9368762
Cancer Cell. 2003 Mar;3(3):219-31
12676581
Nat Rev Drug Discov. 2005 May;4(5):387-98
15864268
Science. 2003 Dec 5;302(5651):1775-9
14657501
Annu Rev Cell Dev Biol. 2005;21:247-69
16212495
Cell. 2007 Jun 1;129(5):865-77
17540168
Science. 1996 Nov 22;274(5291):1374-6
8910277
Cancer Res. 2004 Dec 15;64(24):8994-9001
15604264
Curr Biol. 2006 Dec 19;16(24):2466-72
17174923
Traffic. 2005 Nov;6(11):957-66
16190977
Oncogene. 2007 Jun 21;26(29):4295-305
17213802
Nat Rev Mol Cell Biol. 2003 Jun;4(6):446-56
12778124
J Cell Biol. 2007 Jan 1;176(1):35-42
17190792
Methods Enzymol. 2006;406:437-47
16472676
Nat Struct Mol Biol. 2009 Jan;16(1):23-9
19079265
Cell Signal. 1999 Aug;11(8):545-54
10433515
Mol Cell Biol. 2003 Jun;23(12):4219-29
12773565
Science. 1996 Jul 12;273(5272):245-8
8662509
Science. 1997 Feb 28;275(5304):1308-11
9036856
J Cell Biol. 2008 Jun 16;181(6):999-1012
18559669
J Cell Biol. 2002 Apr 15;157(2):291-302
11956230
Curr Biol. 1999 Feb 11;9(3):136-45
10021386
Bioessays. 2007 Apr;29(4):356-70
17373658
EMBO J. 2002 Oct 1;21(19):5088-96
12356725
Mol Biol Cell. 1999 Aug;10(8):2481-91
10436006
Mol Biol Cell. 2007 Apr;18(4):1242-52
17267693
J Biol Chem. 2004 Jan 16;279(3):1885-91
14559914