Transforming growth factor-alpha enhances cyclin D1 transcription through the binding of early growth response protein to a cis-regulatory element in the cyclin D1 promoter.
Cyclin D1 is a critical oncogene involved in the regulation of progression through the G1 phase of the cell cycle, thereby contributing to cell proliferation. This is mediated through interaction of cyclin D1 with its catalytic partners, the cyclin-dependent kinases, and the subsequent phosphorylation of the retinoblastoma protein. Cyclin D1, in turn, is regulated by mitogenic stimuli. We demonstrate that transforming growth factor-alpha (TGFalpha) induces cyclin D1 mRNA in esophageal squamous epithelial cells, and this appears to correlate with increased cyclin D1 protein expression and cyclin-dependent kinase 6 activity. The induction of cyclin D1 transcription by TGFalpha is mediated in part through the induction of the early growth response protein (Egr-1) and its subsequent binding of Egr-1 to a cis-regulatory region spanning nucleotides -144 to -104 of the cyclin D1 promoter. The Egr-1 binding activity to the cyclin D1 promoter appears to require de novo protein synthesis and is not influenced by Sp1 binding to overlapping Sp1 motifs. Taken together, these data provide evidence that TGFalpha enhances cyclin D1 transcription through the induction of Egr-1 binding to a cis-regulatory region in the cyclin D1 promoter. This has important mechanistic implications into the transcriptional regulation of cyclin D1 by an essential proproliferative growth factor and cell cycle progression.
Yan
Y X
YX
Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Nakagawa
H
H
Lee
M H
MH
Rustgi
A K
AK
D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D051765:Early Growth Response Transcription Factors; D016193:G1 Phase; D006801:Humans; D017874:Immediate-Early Proteins; D051741:Kruppel-Like Transcription Factors; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015183:Restriction Mapping; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D051765:Early Growth Response Transcription Factors; D017874:Immediate-Early Proteins; C098111:KLF10 protein, human; D051741:Kruppel-Like Transcription Factors; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D014157:Transcription Factors; D016211:Transforming Growth Factor alpha; D019938:Cyclin D1; D003513:Cycloheximide; D017346:Protein Serine-Threonine Kinases; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases