Epithelial Protein Lost in Neoplasm alpha (Eplin-alpha) is transcriptionally regulated by G-actin and MAL/MRTF coactivators.
Epithelial Protein Lost in Neoplasm alpha is a novel cytoskeleton-associated tumor suppressor whose expression inversely correlates with cell growth, motility, invasion and cancer mortality. Here we show that Eplin-alpha transcription is regulated by actin-MAL-SRF signalling. Upon signal induction, the coactivator MAL/MRTF is released from a repressive complex with monomeric actin, binds the transcription factor SRF and activates target gene expression. In a transcriptome analysis with a combination of actin binding drugs which specifically and differentially interfere with the actin-MAL complex (Descot et al., 2009), we identified Eplin to be primarily controlled by monomeric actin. Further analysis revealed that induction of the Eplin-alpha mRNA and its promoter was sensitive to drugs and mutant actins which stabilise the repressive actin-MAL complex. In contrast, the Eplin-beta isoform remained unaffected. Knockdown of MRTFs or dominant negative MAL which inhibits SRF-mediated transcription impaired Eplin-alpha expression. Conversely, constitutively active mutant actins and MAL induced Eplin-alpha. MAL and SRF were bound to a consensus SRF binding site of the Eplin-alpha promoter; the recruitment of MAL to this region was enhanced severalfold upon induction. The tumor suppressor Eplin-alpha is thus a novel cytoskeletal target gene transcriptionally regulated by the actin-MAL-SRF pathway, which supports a role in cancer biology.
AG Regulation of Gene Expression, Department of Molecular Biology, Max-Planck-Institute of Biochemistry, D-82152 Martinsried, Germany.
Laura
L
Leitner
Dmitry
D
Shaposhnikov
Arnaud
A
Descot
Reinhard
R
Hoffmann
Guido
G
Posern
D000199:Actins / Q000378:metabolism*; D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D051379:Mice; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic
D000199:Actins; D003598:Cytoskeletal Proteins; C485741:D15Ertd366e protein, mouse; C511173:Mrtfa protein, mouse; D026362:Serum Response Factor; D015534:Trans-Activators