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Deregulated expression of cyclin D1 overrides antimitogenic signals
L A Martinez1, Y Chen, A Pavone
1The University of Texas MD Anderson Cancer Research Center, Science Park-Research Division, Park Road 1-C, Smithville, Texas, TX 78957, USA.
Abstract:
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.
Insights
High cyclin D1 expression in epithelial neoplasms may overcome transforming growth factor beta1 (TGFbeta-1) growth inhibition. Overexpressing cyclin D1 in mouse keratinocytes partially resisted TGFbeta-1-induced growth arrest, suggesting a role in cancer progression.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Epithelial neoplasms often show high transforming growth factor beta1 (TGFbeta-1) expression, suggesting acquired tolerance to its growth-inhibitory effects.
- Cyclin D1 is highly expressed in murine skin tumors alongside TGFbeta-1, prompting investigation into its role in overriding growth arrest.
Purpose of the Study:
- To investigate whether cyclin D1 can override TGFbeta-1-induced growth arrest in primary murine keratinocytes.
- To determine the mechanisms by which cyclin D1 influences TGFbeta-1 signaling and cell cycle regulation.
Main Methods:
- Treatment of primary murine keratinocytes with TGFbeta-1 to assess cyclin D1 expression.
- Utilizing primary keratinocytes from transgenic mice overexpressing cyclin D1 (K5-D1 mice) to evaluate resistance to TGFbeta-1.
- Analysis of cell cycle protein complexes, TGFbeta receptors, and associated kinase activity.
Main Results:
- TGFbeta-1 rapidly suppressed cyclin D1 mRNA and protein levels in wild-type keratinocytes, identifying it as an early target of growth suppression.
- K5-D1 keratinocytes exhibited partial resistance to TGFbeta-1-induced growth inhibition.
- Resistance was linked to alterations in cyclin/cdk/inhibitor complexes and differential cdk-associated kinase activity, not TGFbeta receptor expression.
Conclusions:
- Early suppression of cyclin D1 is a critical mechanism of TGFbeta-1-mediated growth inhibition in keratinocytes.
- Deregulated cyclin D1 expression can partially override TGFbeta-1 growth inhibitory signals by altering cell cycle machinery.
- These findings highlight a potential pathway for cancer cells to evade growth control mechanisms.