CDK4 regulation by TNFR1 and JNK is required for NF-kappaB-mediated epidermal growth control.
Nuclear factor kappaB (NF-kappaB) mediates homeostatic growth inhibition in the epidermis, and a loss of NF-kappaB function promotes proliferation and oncogenesis. To identify mechanisms responsible for these effects, we impaired NF-kappaB action in the epidermis by three different genetic approaches, including conditional NF-kappaB blockade. In each case, epidermal hyperplasia was accompanied by an increase in both protein levels and tissue distribution of the G1 cell cycle kinase, CDK4. CDK4 up-regulation required intact TNFR1 and c-Jun NH2-terminal kinase ( JNK) function. Cdk4 gene deletion concomitant with conditional NF-kappaB blockade demonstrated that CDK4 is required for growth deregulation. Therefore, epidermal homeostasis depends on antagonist regulation of CDK4 expression by NF-kappaB and TNFR1/ JNK.[1]References
- CDK4 regulation by TNFR1 and JNK is required for NF-kappaB-mediated epidermal growth control. Zhang, J.Y., Tao, S., Kimmel, R., Khavari, P.A. J. Cell Biol. (2005) [Pubmed]
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