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  • The EMBO Journal (2003) 22, 2741 - 2751
  • doi:10.1093/emboj/cdg271

The magnitude of hedgehog signaling activity defines skin tumor phenotype

Vladimir Grachtchouk1,4, Marina Grachtchouk1,4, Lori Lowe1,2, Tim Johnson1, Lebing Wei1, Aiqin Wang1, Fred de Sauvage3 and Andrzej A. Dlugosz1

  1. Comprehensive Cancer Center and Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
  2. Comprehensive Cancer Center and Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
  3. Department of Molecular Oncology, Genentech, South San Francisco, CA 94080, USA
  4. V.Grachtchouk and M.Grachtchouk contributed equally to this work

Correspondence to:

Andrzej A. Dlugosz, E-mail: dlugosza@umich.edu

Received 23 October 2002; Accepted 9 April 2003; Revised 4 March 2003

Gain-of-function mutations in SMO have been implicated in constitutive activation of the hedgehog signaling pathway in human basal cell carcinomas (BCCs). We used a truncated keratin 5 (DeltaK5) promoter to assess the potential role of the human M2SMO mutant in BCC development in adult transgenic mice. DeltaK5-M2SMO mouse epidermis is hyperproliferative, ex presses BCC protein markers and gives rise to numerous epithelial downgrowths invading the underlying dermis. Lesions strikingly similar to human basaloid follicular hamartomas develop, but BCCs do not arise even in elderly mice. Hedgehog target gene transcripts were only modestly upregulated in mouse and human follicular hamartomas, in contrast to the high levels detected in BCCs. Cyclins D1 and D2 were selectively upregulated in mouse BCCs. Our data suggest that the levels of hedgehog pathway activation and G1 cyclins are major determinants of tumor phenotype in skin, and strongly implicate deregulated hedgehog signaling in the genesis of human basaloid follicular hamartomas. Expression of an activated SMO mutant in keratinocytes appears to be insufficient for the development and/or maintenance of full-blown BCCs.

  • Keywords:

    • basal cell carcinoma,
    • epidermis,
    • follicular hamartoma,
    • hedgehog,
    • smoothened