A CRE and the region occupied by a protein induced by growth factors contribute to up-regulation of cyclin D1 expression in hepatocytes.
Induction of cyclin D1 expression is a critical feature of growth factor-induced cell proliferation in hepatocytes. To clarify the mechanisms regulating cyclin D1 gene expression, we isolated the rat cyclin D1 gene and analyzed the transcriptional regulatory elements in rat hepatoma cells and primary cultured rat hepatocytes. Two transcriptional regulatory regions were analyzed. One was mapped to a cAMP-responsive element (CRE) at position -41bp and was occupied by a CRE-binding protein (CREB), resulting in cyclin D1 expression. Another (CD1E0.7), located at -753bp, revealed high homology with binding sites for the Ets family, the hepatocyte nuclear factor-3beta, or the nuclear factor of activated T cells. However, CD1E0.7 did not interact with these nuclear factors and specific interaction with a protein extracted from growth factor-treated rat hepatocytes in primary cultures. These results indicate that CREB binds to the CRE and mediates activation of the cyclin D1 promoter, and suggest that CD1E0.7 may be possibly occupied by a protein induced by growth factors in hepatocytes.
Moriuchi
Akihiro
A
Department of Internal Medicine II, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
Ido
Akio
A
Nagata
Yoshiko
Y
Nagata
Kenji
K
Uto
Hirofumi
H
Hasuike
Satoru
S
Hori
Takeshi
T
Hirono
Shuichi
S
Hayashi
Katsuhiro
K
Tsubouchi
Hirohito
H
D024506:5' Flanking Region; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D019938:Cyclin D1 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006133:Growth Substances / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D051381:Rats; D017208:Rats, Wistar; D020218:Response Elements; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D006133:Growth Substances; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; D019938:Cyclin D1; D000242:Cyclic AMP