Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition. Export

@article{citeulike:5960954, abstract = {The proteasome controls a plethora of survival factors in all mammalian cells analyzed to date. Therefore, it is puzzling that proteasome inhibitors such as bortezomib can display a preferential toxicity toward malignant cells. In fact, proteasome inhibitors have the salient feature of promoting a dramatic induction of the proapoptotic protein NOXA in a tumor cell-restricted manner. However, the molecular determinants that control this specific regulation of NOXA are unknown. Here, we show that the induction of NOXA by bortezomib is directly dependent on the oncogene c-MYC. This requirement for c-MYC was found in a variety of tumor cell types, in marked contrast with dispensable roles of p53, HIF-1alpha, and E2F-1 (classical proteasomal targets that can regulate NOXA mRNA under stress). Conserved MYC-binding sites identified at the NOXA promoter were validated by ChIP and reporter assays. Down-regulation of the endogenous levels of c-MYC abrogated the induction of NOXA in proteasome-defective tumor cells. Conversely, forced expression of c-MYC enabled normal cells to accumulate NOXA and subsequently activate cell death programs in response to proteasome blockage. c-MYC is itself a proteasomal target whose levels or function are invariably up-regulated during tumor progression. Our data provide an unexpected function of c-MYC in the control of the apoptotic machinery, and reveal a long sought-after oncogenic event conferring sensitivity to proteasome inhibition.}, author = {Nikiforov, Mikhail A. and Riblett, Marybeth and Tang, Wen-Hua H. and Gratchouck, Vladimir and Zhuang, Dazhong and Fernandez, Yolanda and Verhaegen, Monique and Varambally, Sooryanarayana and Chinnaiyan, Arul M. and Jakubowiak, Andrzej J. and Soengas, Maria S.}, citeulike-article-id = {5960954}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0708380104}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18042711}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18042711}, day = {4}, doi = {10.1073/pnas.0708380104}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, keywords = {cancer, myc, proteasome}, month = {December}, number = {49}, pages = {19488--19493}, posted-at = {2009-10-18 04:34:29}, priority = {2}, title = {Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition.}, url = {http://dx.doi.org/10.1073/pnas.0708380104}, volume = {104}, year = {2007} }

TY - JOUR ID - citeulike:5960954 L3 - citeulike-article-id:5960954 N2 - The proteasome controls a plethora of survival factors in all mammalian cells analyzed to date. Therefore, it is puzzling that proteasome inhibitors such as bortezomib can display a preferential toxicity toward malignant cells. In fact, proteasome inhibitors have the salient feature of promoting a dramatic induction of the proapoptotic protein NOXA in a tumor cell-restricted manner. However, the molecular determinants that control this specific regulation of NOXA are unknown. Here, we show that the induction of NOXA by bortezomib is directly dependent on the oncogene c-MYC. This requirement for c-MYC was found in a variety of tumor cell types, in marked contrast with dispensable roles of p53, HIF-1alpha, and E2F-1 (classical proteasomal targets that can regulate NOXA mRNA under stress). Conserved MYC-binding sites identified at the NOXA promoter were validated by ChIP and reporter assays. Down-regulation of the endogenous levels of c-MYC abrogated the induction of NOXA in proteasome-defective tumor cells. Conversely, forced expression of c-MYC enabled normal cells to accumulate NOXA and subsequently activate cell death programs in response to proteasome blockage. c-MYC is itself a proteasomal target whose levels or function are invariably up-regulated during tumor progression. Our data provide an unexpected function of c-MYC in the control of the apoptotic machinery, and reveal a long sought-after oncogenic event conferring sensitivity to proteasome inhibition. IS - 49 JF - Proceedings of the National Academy of Sciences of the United States of America SN - 1091-6490 EP - 19493 TI - Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition. VL - 104 SP - 19488 KW - cancer KW - myc KW - proteasome AU - Nikiforov, Mikhail AU - Riblett, Marybeth AU - Tang, Wen-Hua AU - Gratchouck, Vladimir AU - Zhuang, Dazhong AU - Fernandez, Yolanda AU - Verhaegen, Monique AU - Varambally, Sooryanarayana AU - Chinnaiyan, Arul AU - Jakubowiak, Andrzej AU - Soengas, Maria PY - 2007/12/04/ UR - http://dx.doi.org/10.1073/pnas.0708380104 ER -