MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells.
MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells.
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DOI：
10.1038/onc.2012.43
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发表时间：
2013-01-10
期刊：
影响因子：
8
通讯作者：
Lichtenstein, A.
中科院分区：
文献类型：
--
作者：
Shi, Y.;Frost, P.;Hoang, B.;Yang, Y.;Fukunaga, R.;Gera, J.;Lichtenstein, A.
When mTOR inhibitor rapalogs prevent cap-dependent translation of cell cycle proteins like cmyc, continuing tumor cell growth depends on cap-independent translation, which is mediated by internal ribosome entry sites (IRESes) located in the 5′UTR of transcripts. To investigate if rapalog-induced activation of MNK kinases played a role in such IRES activity, we studied multiple myeloma (MM) cells. Rapamycin activated MNK1 kinase activity in MM cell lines and primary specimens by a MAPK-dependent mechanism. Pharmacological inhibition of MNK activity or genetic silencing of MNK1 prevented a rapalog-induced upregulation of c-myc IRES activity. Although rapamycin, used alone, had little effect on myc protein expression, when combined with a MNK inhibitor, myc protein expression was abrogated. In contrast, there was no inhibition of myc RNA, consistent with an effect on myc translation. In a rapamycin-resistant MM cell lines as well as a resistant primary MM specimen, co-exposure to a MNK inhibitor or MNK1 knockdown significantly sensitized cells for rapamycin-induced cytoreduction. Studies in MNK-null murine embryonic fibroblasts additionally supported a role for MNK kinases in rapamycin-induced myc IRES stimulation. These results indicate that MNK kinase activity plays a critical role in the fail safe mechanism of IRES-dependent translation when mTOR is inhibited. As kinase activity also regulated sensitivity to rapamycin, the data also provide a rationale for therapeutically targeting MNK kinases for combined treatment with mTOR inhibitors.
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影响因子：
5.7
作者：
Frost P;Shi Y;Hoang B;Gera J;Lichtenstein A
通讯作者：
Lichtenstein A
影响因子：
4.8
作者：
Gera, JF;Mellinghoff, IK;Lichtenstein, AK
通讯作者：
Lichtenstein, AK
影响因子：
64.5
作者：
Peterson TR;Laplante M;Thoreen CC;Sancak Y;Kang SA;Kuehl WM;Gray NS;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
5.3
作者：
Scheper, GC;Parra, JL;Proud, CG
通讯作者：
Proud, CG
影响因子：
8
作者：
Evans, JR;Mitchell, SA;Willis, AE
通讯作者：
Willis, AE