IKKalpha is a critical coregulator of a Smad4-independent TGFbeta-Smad2/3 signaling pathway that controls keratinocyte differentiation.
Cell-cycle exit and differentiation of suprabasal epidermal keratinocytes require nuclear IkappaB kinase alpha (IKKalpha), but not its protein kinase activity. IKKalpha also is a suppressor of squamous cell carcinoma (SCC), but its mode of action remains elusive. Postulating that IKKalpha may serve as a transcriptional regulator in keratinocytes, we searched for cell-cycle-related genes that could illuminate this function. IKKalpha was found to control several Myc antagonists, including Mad1, Mad2, and Ovol1, through the association with TGFbeta-regulated Smad2/3 transcription factors and is required for Smad3 recruitment to at least one of these targets. Surprisingly, Smad2/3-dependent Mad1 induction and keratinocyte differentiation are independent of Smad4, the almost universal coregulator of canonical TGFbeta signaling. IKKalpha also is needed for nuclear accumulation of activated Smad2/3 in the epidermis, and Smad2/3 are required for epidermal differentiation. We suggest that a TGFbeta-Smad2/3-IKKalpha axis is a critical Smad4-independent regulator of keratinocyte proliferation and differentiation.
Descargues
Pascal
P
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA.
Sil
Alok K
AK
Sano
Yuji
Y
Korchynskyi
Olexandr
O
Han
Gangwen
G
Owens
Philip
P
Wang
Xiao-Jing
XJ
Karin
Michael
M
D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation / Q000187:drug effects*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051901:Smad4 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D002843:Chromatin; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D051550:I-kappa B Kinase