期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 31, 页码 10853-10858出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0804821105
关键词
rapamycin response; Tsc2 loss; apoptosis; lymphoma; Akt
资金
- NCI NIH HHS [P01 CA087497, P30 CA008748, CA87497] Funding Source: Medline
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 mu-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 mu-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.
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