Deregulated expression of cyclin D1 overrides antimitogenic signals.
Several types of epithelial neoplasms exhibit high expression of transforming growth factor beta1 (TGFbeta-1), indicating that they have acquired tolerance to this normally growth inhibitory cytokine. Since cyclin D1 is expressed at high levels in murine skin tumors coincident with high levels of TGFbeta-1 expression, we hypothesized that cyclin D1 may override TGFbeta-1 induced growth arrest. We observed that in primary murine keratinocytes treated with TGFbeta-1, cyclin D1 is quickly suppressed at both the mRNA and protein level. Since changes in other cell cycle proteins occur at a later time during TGFbeta-1 treatment, the early suppression of cyclin D1 suggests that this gene is a critical target for TGFbeta-1 growth suppression. Using primary keratinocytes from transgenic mice that overexpress cyclin D1 (K5-D1 mice), we observed partial resistance to TGFbeta-1 growth inhibition. This resistance involves changes in the cyclin/cdk/inhibitor complexes rather than differences in expression of the TGFbeta receptors or signaling. Comparison of cdk associated kinase activity between wild-type and K5-D1 cells shows differential regulation. We conclude that deregulated cyclin D1 and subsequent alterations in cell cycle machinery provides keratinocytes the ability to at least partially override growth inhibitory signals.
Martinez
L A
LA
The University of Texas MD Anderson Cancer Research Center, Science Park-Research Division, Park Road 1-C, Smithville, Texas, TX 78957, USA.
Chen
Y
Y
Pavone
A
A
Fischer
S M
SM
Conti
C J
CJ
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000502:physiology; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000502:physiology; D006131:Growth Inhibitors / Q000502:physiology*; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology
D006131:Growth Inhibitors; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D019938:Cyclin D1; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases