Mills, J. R., Hippo, Y., Robert, F., Chen, S. M. H., Malina, A., Lin, C. J., Trojahn, U., Wendel, H. G., Charest, A., Bronson, R. T., Kogan, S. C., Nadon, R., Housman, D. E., Lowe, S. W., Pelletier, J. (August 2008) mTORC1 promotes survival through translational control of Mcl-1. Proc Natl Acad Sci U S A, 105 (31). pp. 10853-10858.
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Abstract
Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is a frequent occurrence in human cancers and a major promoter of chemotherapeutic resistance. Inhibition of one downstream target in this pathway, mTORC1, has shown potential to improve chemosensitivity. However, the mechanisms and genetic modifications that confer sensitivity to mTORC1 inhibitors remain unclear. Here, we demonstrate that loss of TSC2 in the E?-myc murine lymphoma model leads to mTORC1 activation and accelerated oncogenesis caused by a defective apoptotic program despite compromised AKT phosphorylation. Tumors from Tsc2+/-E?-Myc mice underwent rapid apoptosis upon blockade of mTORC1 by rapamycin. We identified myeloid cell leukemia sequence 1 (Mcl-1), a bcl-2 like family member, as a translationally regulated genetic determinant of mTORC1-dependent survival. Our results indicate that the extent by which rapamycin can modulate expression of Mcl-1 is an important feature of the rapamycin response. © 2008 by The National Academy of Sciences of the USA.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Akt Apoptosis Lymphoma Rapamycin response Tsc2 loss |
| Subjects: | diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > translation |
| CSHL Authors: | |
| Communities: | CSHL labs > Lowe lab |
| Depositing User: | Matt Covey |
| Date: | 5 August 2008 |
| Date Deposited: | 26 Feb 2013 16:19 |
| Last Modified: | 08 Nov 2017 21:31 |
| PMCID: | PMC2504845 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/27574 |
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