Gene interactions and pathways from curated databases and text-mining
J Biol Chem 2011, PMID: 21177869

mTOR-dependent regulation of PHLPP expression controls the rapamycin sensitivity in cancer cells.

Liu, Jianyu; Stevens, Payton D; Gao, Tianyan

PHLPP belongs to a novel family of protein phosphatases that serve as negative regulators of Akt. There are two isoforms, PHLPP1 and PHLPP2, identified in this family. Our previous studies indicated a tumor suppressor role of both PHLPP isoforms in colon cancer. Here we report that the expression of PHLPP is controlled by mTOR-dependent protein translation in colon and breast cancer cells. Treating cells with rapamycin or knockdown of mTOR using RNAi results in a marked decrease of PHLPP protein expression. In contrast, stable knockdown of TSC2, a negative regulator of mTOR activity, increases PHLPP expression. The rapamycin-mediated down-regulation of PHLPP is blocked by expression of a rapamycin-insensitive mutant of p70S6K. In addition, depletion of 4E-BP1 expression by RNAi results in an increase of PHLPP expression and resistance to rapamycin-induced down-regulation. Moreover, inhibition of mTOR activity by amino acid or glucose starvation reduces PHLPP expression in cells. Functionally, we show that rapamycin-mediated inhibition of PHLPP expression contributes to rapamycin resistance in colon cancer cells. Thus, our studies identify a compensatory feedback regulation in which the activation of Akt is inhibited by up-regulation of PHLPP through mTOR, and this mTOR-dependent expression of PHLPP subsequently determines the rapamycin sensitivity of cancer cells.

Diseases/Pathways annotated by Medline MESH: Colonic Neoplasms
Document information provided by NCBI PubMed

Text Mining Data

PHLPP ⊣ mTOR: " mTOR dependent regulation of PHLPP expression controls the rapamycin sensitivity in cancer cells "

mTOR — TSC2: " In contrast, stable knockdown of TSC2 , a negative regulator of mTOR activity, increases PHLPP expression "

PHLPP → p70S6K: " The rapamycin mediated down-regulation of PHLPP is blocked by expression of a rapamycin-insensitive mutant of p70S6K "

PHLPP → mTOR: " Moreover, inhibition of mTOR activity by amino acid or glucose starvation reduces PHLPP expression in cells "

Akt ⊣ PHLPP: " Thus, our studies identify a compensatory feedback regulation in which the activation of Akt is inhibited by up-regulation of PHLPP through mTOR, and this mTOR dependent expression of PHLPP subsequently determines the rapamycin sensitivity of cancer cells "

PHLPP → mTOR: " Thus, our studies identify a compensatory feedback regulation in which the activation of Akt is inhibited by up-regulation of PHLPP through mTOR, and this mTOR dependent expression of PHLPP subsequently determines the rapamycin sensitivity of cancer cells "

Manually curated Databases

No curated data.