Notch1 is an effector of Akt and hypoxia in melanoma development

Barbara Bedogni, James A. Warneke, Brian J. Nickoloff, Amato J. Giaccia, Marianne Broome Powell

Research output: Contribution to journalArticle

154 Citations (Scopus)

Abstract

Melanomas are highly aggressive neoplasms resistant to most conventional therapies. These tumors result from the interaction of altered intracellular tumor suppressors and oncogenes with the microenvironment in which these changes occur. We previously demonstrated that physiologic skin hypoxia contributes to melanomagenesis in conjunction with Akt activation. Here we show that Notch1 signaling is elevated in human melanoma samples and cell lines and is required for Akt and hypoxia to transform melanocytes in vitro. Notch1 facilitated melanoma development in a xenograft model by maintaining cell proliferation and by protecting cells from stress-induced cell death. Hyperactivated PI3K/Akt signaling led to upregulation of Notch1 through NF-κB activity, while the low oxygen content normally found in skin increased mRNA and protein levels of Notch1 via stabilization of HIF-1α. Taken together, these findings demonstrate that Notch1 is a key effector of both Akt and hypoxia in melanoma development and identify the Notch signaling pathway as a potential therapeutic target in melanoma treatment.

Original languageEnglish (US)
Pages (from-to)3660-3670
Number of pages11
JournalJournal of Clinical Investigation
Volume118
Issue number11
DOIs
StatePublished - Nov 3 2008
Externally publishedYes

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Melanoma
Notch1 Receptor
Neoplasms
Skin
Melanocytes
Phosphatidylinositol 3-Kinases
Oncogenes
Heterografts
Cell Death
Up-Regulation
Cell Proliferation
Hypoxia
Oxygen
Cell Line
Messenger RNA
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bedogni, B., Warneke, J. A., Nickoloff, B. J., Giaccia, A. J., & Powell, M. B. (2008). Notch1 is an effector of Akt and hypoxia in melanoma development. Journal of Clinical Investigation, 118(11), 3660-3670. https://doi.org/10.1172/JCI36157

Notch1 is an effector of Akt and hypoxia in melanoma development. / Bedogni, Barbara; Warneke, James A.; Nickoloff, Brian J.; Giaccia, Amato J.; Powell, Marianne Broome.

In: Journal of Clinical Investigation, Vol. 118, No. 11, 03.11.2008, p. 3660-3670.

Research output: Contribution to journalArticle

Bedogni, B, Warneke, JA, Nickoloff, BJ, Giaccia, AJ & Powell, MB 2008, 'Notch1 is an effector of Akt and hypoxia in melanoma development', Journal of Clinical Investigation, vol. 118, no. 11, pp. 3660-3670. https://doi.org/10.1172/JCI36157
Bedogni, Barbara ; Warneke, James A. ; Nickoloff, Brian J. ; Giaccia, Amato J. ; Powell, Marianne Broome. / Notch1 is an effector of Akt and hypoxia in melanoma development. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 11. pp. 3660-3670.
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