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.
Duke Scholars
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Receptors, Tumor Necrosis Factor, Type I
- Proto-Oncogene Proteins
- Protein Serine-Threonine Kinases
- NF-kappaB-Inducing Kinase
- Mitogen-Activated Protein Kinase Kinases
- Mice
- MAP Kinase Kinase 4
- Keratinocytes
- JNK Mitogen-Activated Protein Kinases
- Hyperplasia
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Receptors, Tumor Necrosis Factor, Type I
- Proto-Oncogene Proteins
- Protein Serine-Threonine Kinases
- NF-kappaB-Inducing Kinase
- Mitogen-Activated Protein Kinase Kinases
- Mice
- MAP Kinase Kinase 4
- Keratinocytes
- JNK Mitogen-Activated Protein Kinases
- Hyperplasia