期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 38, 页码 15840-15845出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1019312108
关键词
cell survival; endoplasmic reticulum stress
资金
- National Natural Science Foundation of China [31030046]
- Ministry of Science and Technology of China [2010CB912804, 2011CB966302, 2011CBA01103]
- Chinese Academy of Sciences [XDA01020104]
- National Health and Medical Research Council (NHMRC)
- Cancer Council of New South Wales
- Cancer Institute New South Wales, Australia
The tumor suppressor p53 is activated in response to cellular stress to prevent malignant transformation by activation of the DNA repair machinery to preserve the cell, or by induction of apoptosis to eliminate the cell should the damage prove irrevocable. The gene encoding p53 frequently undergoes inactivating mutations in many human cancers, but WT p53 is often expressed at high levels in melanoma, which, as judged from the malignant nature of the disease, fails to act as an effective tumor suppressor. Here we show that p53 directly up-regulates microRNA-149* (miR-149*) that in turn targets glycogen synthase kinase-3 alpha, resulting in increased expression of Mcl-1 and resistance to apoptosis in melanoma cells. Although deficiency in miR-149* undermined survival of melanoma cells and inhibited melanoma growth in a mouse xenograft model, elevated expression of miR-149* was found in fresh human metastatic melanoma isolates, which was associated with decreased glycogen synthase kinase-3 alpha and increased Mcl-1. These results reveal a p53-dependent, miR-149*-mediated pathway that contributes to survival of melanoma cells, provides a rational explanation for the ineffectiveness of p53 to suppress melanoma, and identifies the expression of miR-149* as a mechanism involved in the increased expression of Mcl-1 in melanoma cells.
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