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.
Zhang
Jennifer Y
JY
Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA 94304, USA.
Tao
Shiying
S
Kimmel
Robin
R
Khavari
Paul A
PA
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D048670:MAP Kinase Kinase 4; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D000097782:NF-kappaB-Inducing Kinase; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse