Cripto-1 alters keratinocyte differentiation via blockade of transforming growth factor-β1 signaling: Role in skin carcinogenesis

Anjali Shukla, Yan Ho, Xin Liu, Andrew Ryscavage, Adam B. Glick

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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)-β1 signaling pathway using the ALK5 kinase inhibitor SB431542 and dominant negative TGF-β type II receptor, respectively, had similar effects on keratinocyte differentiation. Our results show that Cripto-1 could block TGF-β1 receptor binding, phosphorylation of Smad2 and Smad3, TGF-β-responsive luciferase reporter activity, and TGF-β1-mediated senescence of keratinocytes. We suggest that inhibition of TGF-β1 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.

Original languageEnglish (US)
Pages (from-to)509-516
Number of pages8
JournalMolecular Cancer Research
Volume6
Issue number3
DOIs
StatePublished - Mar 1 2008

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Transforming Growth Factors
Keratinocytes
Carcinogenesis
Skin
Growth Factor Receptors
Neoplasms
Keratin-1
Keratin-8
Differentiation Antigens
Papilloma
Luciferases
Epidermal Growth Factor
Epidermis
Carcinogens
Embryonic Development
Phosphotransferases
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

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abstract = "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)-β1 signaling pathway using the ALK5 kinase inhibitor SB431542 and dominant negative TGF-β type II receptor, respectively, had similar effects on keratinocyte differentiation. Our results show that Cripto-1 could block TGF-β1 receptor binding, phosphorylation of Smad2 and Smad3, TGF-β-responsive luciferase reporter activity, and TGF-β1-mediated senescence of keratinocytes. We suggest that inhibition of TGF-β1 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.",
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Cripto-1 alters keratinocyte differentiation via blockade of transforming growth factor-β1 signaling : Role in skin carcinogenesis. / Shukla, Anjali; Ho, Yan; Liu, Xin; Ryscavage, Andrew; Glick, Adam B.

In: Molecular Cancer Research, Vol. 6, No. 3, 01.03.2008, p. 509-516.

Research output: Contribution to journalArticle

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