Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Constitutive activation of Akt characterizes a high percentage of human melanomas and represents a poor prognostic factor of the disease. We show that Akt transforms melanocytes only in a hypoxic environment, which is found in normal skin. The synergy between Akt and hypoxia is HIF1alpha mediated. Inhibition of HIF1alpha decreases Akt transformation capacity in hypoxia and tumor growth in vivo, while overexpression of HIF1alpha allows anchorage-independent growth in normoxia and development of more aggressive tumors. Finally, we show that mTOR activity is necessary to maintain the transformed phenotype by sustaining HIF1alpha activity. Taken together, these findings demonstrate that Akt hyperactivation and HIF1alpha induction by normally occurring hypoxia in the skin significantly contribute to melanoma development.

Original publication

DOI

10.1016/j.ccr.2005.11.005

Type

Journal article

Journal

Cancer Cell

Publication Date

12/2005

Volume

8

Pages

443 - 454

Keywords

Animals, Cell Hypoxia, Cell Line, Cell Proliferation, Cell Transformation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Male, Melanocytes, Mice, Mice, Knockout, Mice, SCID, Oxygen, Phenotype, Protein Kinases, Proto-Oncogene Proteins c-akt, Sirolimus, Skin, TOR Serine-Threonine Kinases