C-terminal-binding protein corepresses epithelial and proapoptotic gene expression programs.
The genesis of carcinoma cells often involves epithelial-to-mesenchymal transitions and the acquisition of apoptosis resistance, but it is unclear whether these alterations are controlled coordinately or independently. Our previously reported effects of adenovirus E1a in human tumor cells raised the possibility that the E1a-interacting corepressor protein C-terminal-binding protein (CtBP) might selectively repress epithelial cell adhesion and proapoptotic genes. Here, we report that CtBP-knockout cells were hypersensitive to apoptosis. Correspondingly, microarray analysis of CtBP-knockout vs. CtBP-rescued mouse embryo fibroblasts revealed that many epithelial-specific and proapoptotic genes were indeed regulated by CtBP. Neither the apoptosis nor the repression activities of CtBP required histidine-315, suggesting that the proposed dehydrogenase activity is not essential for CtBP function. The results presented herein establish two functional roles of CtBP: to corepress epithelial genes, thus permitting epithelial-to-mesenchymal transitions, and to modulate the cellular threshold for apoptotic responses.
Grooteclaes
Madeleine
M
The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Deveraux
Quinn
Q
Hildebrand
Jeffrey
J
Zhang
Qinghong
Q
Goodman
Richard H
RH
Frisch
Steven M
SM
D000429:Alcohol Oxidoreductases; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D010088:Oxidoreductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; D010088:Oxidoreductases; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein