ISSN:
1040-452X
Keywords:
Cell proliferation
;
c-myc
;
Retinoblastoma gene
;
Life and Medical Sciences
;
Cell & Developmental Biology
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Biology
Notes:
The predominant effect of TGF-β1 on cell proliferation is inhibition. Earlier studies demonstrated that TGF-β1 inhibition of skin keratinocyte proliferation involves suppression of c-myc transcription and indirect evidence suggested that the protein product of the retinoblastoma gene (pRB) may be involved in this process. Skin keratinocytes transformed by SV40 and human papilloma virus-16 (HPV-16) or HPV-18 resisted growth inhibition and suppression of c-myc mRNA by TGF-β. Transient expression of HPV-16 E7 gene, adenovirus E1A, and SV40 large T antigen (TAg) blocked the TGF-β1 suppression of c-myc transcription. Studies with transformation-defective mutants of E1A and TAg suggested that a cellular protein(s) that interacts with a conserved domain of the DNA tumor virus oncoproteins mediates TGF-β1 suppression of c-myc transcription and keratinocyte growth. Transient expression of pRB in skin keratinocytes repressed human c-myc promoter/CAT transcription as effectively as TGF-β1. The same c-myc promoter region, termed the TGF-β Control Element (TCE), was required for regulation by both TGF-β1 and pRB. TCE bound a cellular protein of approximately 106 kDa and this binding was decreased by TGF-β1 treatment. Our data indicate that pRB can inhibit c-myc transcription and suggest the involvement of cellular factor(s) in addition to pRB in the TGF-β1 pathway for the suppression of c-myc transcription and growth inhibition. The possible involvement of pRB in the TGF-β1 pathway for suppression of c-myc transcription has a number of implications; c-myc is a cellular proto-oncogene involved in positively regulating cell proliferation. TGF-β1 may therefore act through the tumor suppressor gene product, pRB, to negatively regulate c-myc transcription and subsequently cell growth. This would implicate tumor suppressor genes in the response pathway for diffusible growth inhibitors, perhaps analogous to nuclear proto-oncogene involvement in the growth factor pathway. © 1992 Wiley-Liss, Inc.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/mrd.1080320215
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