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Marderosian M, Sharma A, Funk AP, Vartanian R, Masri J, Jo OD, Gera
JF.
Oncogene. 2006 Oct 12;25(47):6277-90
Tristetraprolin regulates Cyclin D1 and c-Myc mRNA stability in
response to rapamycin in an Akt-dependent manner via p38 MAPK signaling.
Department of Research & Development, Greater Los Angeles Veterans
Affairs Healthcare System, Sepulveda, CA 91343, USA.
The differential expression of the critical cell cycle control
proteins cyclin D1 and c-myc has been shown to result in Akt-dependent
hypersensitivity of tumor cells to mTOR inhibitors. We have previously
demonstrated that the differential utilization of internal ribosome entry sites
within the mRNAs of these transcripts allows maintenance of protein synthesis in
the face of rapamycin (rapa) exposure in an Akt-dependent manner. Here, we
demonstrate that in addition to this mechanism, cyclin D1 and c-myc mRNA
stability is also coordinately regulated following rapa treatment depending on
Akt activity status. We identify A/U-rich response elements within the 3'
untranslated regions (UTRs) of these transcripts, which confer the observed
differential stabilities and show that the RNA-binding protein, tristetraprolin
(TTP), interacts with these elements. We also present evidence that TTP
accumulates in response to rapa exposure, binds to the cis-acting elements
within the cyclin D1 and c-myc 3' UTRs and is differentially serine
phosphorylated in an Akt-dependent manner. Furthermore, the differential
phosphorylation status of TTP results in its sequestration by 14-3-3 proteins in
quiescent Akt-containing cells. Finally, siRNA-mediated knockdown of TTP
expression or inhibiting a known regulator of TTP phosphorylation, p38 MAP
kinase, abolishes the effects on cyclin D1 and c-myc mRNA stability. We assume
that the differential control of cyclin D1 and c-myc mRNA stability and
translational efficiency constitutes a coordinate response to rapa contributing
to the maintenance of expression of these determinants in rapa-resistant
quiescent Akt-containing cells following exposure.
PMID: 16702957
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