mTORC1 Activation Blocks BrafV600E-Induced Growth Arrest but Is Insufficient for Melanoma Formation
| Autor: | Manjula Santhanakrishnan, Nicholas Theodosakis, Glenn Merlino, David Dankort, Ildiko Erdelyi, David P. Curley, Laura Huang, Goran Micevic, Marcus Bosenberg, Viswanathan Muthusamy, Nabeel Bardeesy, Martin McMahon, William Damsky, Katrina Meeth, Michael A. Davies, M. Raza Zaidi, James T. Platt, Scott Tighe |
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| Jazyk: | angličtina |
| Předmět: |
Proto-Oncogene Proteins B-raf
Cancer Research Skin Neoplasms Molecular Sequence Data Melanoma Experimental Mechanistic Target of Rapamycin Complex 2 Biology AMP-Activated Protein Kinases Mechanistic Target of Rapamycin Complex 1 Protein Serine-Threonine Kinases mTORC2 Article 03 medical and health sciences Mice 0302 clinical medicine CDKN2A Cell Line Tumor medicine Nevus Animals Humans skin and connective tissue diseases Protein kinase B neoplasms PI3K/AKT/mTOR pathway Cyclin-Dependent Kinase Inhibitor p16 030304 developmental biology Cell Proliferation 0303 health sciences Melanoma TOR Serine-Threonine Kinases Cell Biology Melanocytic nevus medicine.disease digestive system diseases MicroRNAs Oncology 030220 oncology & carcinogenesis Multiprotein Complexes Mutation Cancer research Melanocytes V600E Signal Transduction |
| Zdroj: | Cancer Cell. (1):41-56 |
| ISSN: | 1535-6108 |
| DOI: | 10.1016/j.ccell.2014.11.014 |
| Popis: | Braf(V600E) induces benign, growth-arrested melanocytic nevus development, but also drives melanoma formation. Cdkn2a loss in Braf(V600E) melanocytes in mice results in rare progression to melanoma, but only after stable growth arrest as nevi. Immediate progression to melanoma is prevented by upregulation of miR-99/100, which downregulates mTOR and IGF1R signaling. mTORC1 activation through Stk11 (Lkb1) loss abrogates growth arrest of Braf(V600E) melanocytic nevi, but is insufficient for complete progression to melanoma. Cdkn2a loss is associated with mTORC2 and Akt activation in human and murine melanocytic neoplasms. Simultaneous Cdkn2a and Lkb1 inactivation in Braf(V600E) melanocytes results in activation of both mTORC1 and mTORC2/Akt, inducing rapid melanoma formation in mice. In this model, activation of both mTORC1/2 is required for Braf-induced melanomagenesis. |
| Databáze: | OpenAIRE |
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