Cripto-1 alters keratinocyte differentiation via blockade of transforming growth factor-beta1 signaling: role in skin carcinogenesis.
Cripto-1 is an epidermal growth factor-Cripto/FRL1/Cryptic family member that plays a role in early embryogenesis as a coreceptor for Nodal and is overexpressed in human tumors. Here we report that in the two-stage mouse skin carcinogenesis model, Cripto-1 is highly up-regulated in tumor promoter-treated normal skin and in benign papillomas. Treatment of primary mouse keratinocytes with Cripto-1 stimulated proliferation and induced expression of keratin 8 but blocked induction of the normal epidermal differentiation marker keratin 1, changes that are hallmarks of tumor progression in squamous cancer. Chemical or genetic blockade of the transforming growth factor (TGF)-beta1 signaling pathway using the ALK5 kinase inhibitor SB431542 and dominant negative TGF-beta type II receptor, respectively, had similar effects on keratinocyte differentiation. Our results show that Cripto-1 could block TGF-beta1 receptor binding, phosphorylation of Smad2 and Smad3, TGF-beta-responsive luciferase reporter activity, and TGF-beta1-mediated senescence of keratinocytes. We suggest that inhibition of TGF-beta1 by Cripto-1 may play an important role in altering the differentiation state of keratinocytes and promoting outgrowth of squamous tumors in the mouse epidermis.
Shukla
Anjali
A
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
Ho
Yan
Y
Liu
Xin
X
Ryscavage
Andrew
A
Glick
Adam B
AB
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002294:Carcinoma, Squamous Cell; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D004261:DNA Replication; D004815:Epidermal Growth Factor / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D015603:Keratinocytes / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000503:physiopathology*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000502:physiology
D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D018125:Receptors, Transforming Growth Factor beta; C489450:Tdgf1 protein, mouse; D053773:Transforming Growth Factor beta1; D015127:9,10-Dimethyl-1,2-benzanthracene; D004815:Epidermal Growth Factor; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse