Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway.
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 (HRAS(G12V)) but not its downstream target BRAF (BRAF(V600E)), engaged a rapid cell-cycle arrest that was associated with massive vacuolization and expansion of the ER. However, neither p53, p16(INK4a) nor classical senescence markers--such as foci of heterochromatin or DNA damage--were able to account for the specific response of melanocytes to HRAS(G12V). Instead, HRAS(G12V)-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.
Denoyelle
Christophe
C
Department of Dermatology and Comprehensive Cancer Center, University of Michigan, 1500E Medical Center Drive, 4217 CCGC, Ann Arbor, MI 48109, USA.
Abou-Rjaily
George
G
Bezrookove
Vladimir
V
Verhaegen
Monique
M
Johnson
Timothy M
TM
Fullen
Douglas R
DR
Pointer
Jenny N
JN
Gruber
Stephen B
SB
Su
Lyndon D
LD
Nikiforov
Mikhail A
MA
Kaufman
Randal J
RJ
Bastian
Boris C
BC
Soengas
Maria S
MS
D002453:Cell Cycle; D049109:Cell Proliferation; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D011905:Genes, ras / Q000235:genetics*; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D008544:Melanocytes / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D019941:Cyclin-Dependent Kinase Inhibitor p16; D006570:Heterochromatin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases