IKKalpha is required to maintain skin homeostasis and prevent skin cancer.
It has long been known that excessive mitotic activity due to H-Ras can block keratinocyte differentiation and cause skin cancer. It is not clear whether there are any innate surveillants that are able to ensure that keratinocytes undergo terminal differentiation, preventing the disease. IKKalpha induces keratinocyte terminal differentiation, and its downregulation promotes skin tumor development. However, its intrinsic function in skin cancer is unknown. Here, we found that mice with IKKalpha deletion in keratinocytes develop a thickened epidermis and spontaneous squamous cell-like carcinomas. Inactivation of epidermal growth factor receptor (EGFR) or reintroduction of IKKalpha inhibits excessive mitosis, induces terminal differentiation, and prevents skin cancer through repressing an EGFR-driven autocrine loop. Thus, IKKalpha serves as an innate surveillant.
Liu
Bigang
B
Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
Xia
Xiaojun
X
Zhu
Feng
F
Park
Eunmi
E
Carbajal
Steve
S
Kiguchi
Kaoru
K
DiGiovanni
John
J
Fischer
Susan M
SM
Hu
Yinling
Y
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D066258:Amphiregulin; D000818:Animals; D000831:Animals, Newborn; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000235:genetics; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000235:genetics; D006706:Homeostasis; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology
D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D018124:Receptors, Tumor Necrosis Factor; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; D016283:Proto-Oncogene Proteins p21(ras)
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