Nature Cell Biology
- 8, 1053 - 1063 (2006)
Published online: 10 September 2006; | doi:10.1038/ncb1471
There is an Corrigendum (November 2006) associated with this Article.
Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathwayChristophe Denoyelle1, 6, George Abou-Rjaily1, 6, Vladimir Bezrookove2, 6, Monique Verhaegen1, Timothy M. Johnson1, Douglas R. Fullen3, Jenny N. Pointer4, Stephen B. Gruber4, Lyndon D. Su3, Mikhail A. Nikiforov1, Randal J. Kaufman5, Boris C. Bastian2 & Maria S. Soengas11
Department of Dermatology and Comprehensive Cancer Center, University of Michigan, 1500E Medical Center Drive, 4217 CCGC, Ann Arbor, MI 48109, USA. 2
Departments of Dermatology and Pathology and Comprehensive Cancer Center, University of California San Francisco, UCSF Box 0808, San Francisco, CA 94143, USA. 3
Department of Pathology, University of Michigan, 1500E Medical Center Drive, M5226 MSI, Ann Arbor, MI 48109, USA. 4
Departments of Internal Medicine, Human Genetics and Epidemiology, University of Michigan, 1500E Medical Center Drive, 4301 MSRB III, Ann Arbor, MI 48109, USA
5
Department of Biological Chemistry, University of Michigan and Howard Hughes Medical Institute, 4554 MSRB II, Ann Arbor, MI 48109, USA. 6
These authors contributed equally to this work.
Correspondence should be addressed to Maria S. Soengas soengas@umich.edu Dysfunction of the endoplasmic reticulum (ER) has been reported in a variety of human pathologies, including cancer. However, the contribution of the ER to the early stages of normal cell transformation is largely unknown. Using primary human melanocytes and biopsies of human naevi (moles), we show that the extent of ER stress induced by cellular oncogenes may define the mechanism of activation of premature senescence. Specifically, we found that oncogenic forms of HRAS (HRASG12V) but not its downstream target BRAF (BRAFV600E), engaged a rapid cell-cycle arrest that was associated with massive vacuolization and expansion of the ER. However, neither p53, p16INK4a nor classical senescence markers – such as foci of heterochromatin or DNA damage – were able to account for the specific response of melanocytes to HRASG12V. Instead, HRASG12V-driven senescence was mediated by the ER-associated unfolded protein response (UPR). The impact of HRAS on the UPR was selective, as it was poorly induced by activated NRAS (more frequently mutated in melanoma than HRAS). These results argue against premature senescence as a converging mechanism of response to activating oncogenes and support a direct role of the ER as a gatekeeper of tumour control.
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