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Regulation of anti-apoptotic Bcl-2 family protein Mcl-1 by S6 kinase 2

The anti-apoptotic Bcl-2 family protein myeloid cell leukemia-1 (Mcl-1) plays an important role in breast cancer cell survival and chemoresistance. We have previously shown that knockdown of the 40S ribosomal protein S6 kinase-2 (S6K2), which acts downstream of the mechanistic target of rapamycin co...

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Autores principales: Basu, Alakananda, Sridharan, Savitha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354308/
https://www.ncbi.nlm.nih.gov/pubmed/28301598
http://dx.doi.org/10.1371/journal.pone.0173854
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author Basu, Alakananda
Sridharan, Savitha
author_facet Basu, Alakananda
Sridharan, Savitha
author_sort Basu, Alakananda
collection PubMed
description The anti-apoptotic Bcl-2 family protein myeloid cell leukemia-1 (Mcl-1) plays an important role in breast cancer cell survival and chemoresistance. We have previously shown that knockdown of the 40S ribosomal protein S6 kinase-2 (S6K2), which acts downstream of the mechanistic target of rapamycin complex 1 (mTORC1), enhanced breast cancer cell death by apoptotic stimuli. The increase in cell death by S6K2 depletion was partly due to inactivation of Akt. In the present study, we investigated if S6K2 regulates Mcl-1, which acts downstream of Akt. Silencing of S6K2 but not S6K1 in T47D cells decreased Mcl-1 level, and potentiated apoptosis induced by TRAIL and doxorubicin. Knockdown of S6K2 also decreased the level of anti-apoptotic Bcl-xl. Depletion of the tumor suppressor protein PDCD4 (programmed cell death 4), which regulates translation of several anti-apoptotic proteins, reversed downregulation of Bcl-xl but not Mcl-1 and failed to reverse the effect of S6K2 knockdown on potentiation of doxorubicin-induced apoptosis. Downregulation of Mcl-1 by S6K2 knockdown was partly restored by the proteasome inhibitor MG132. Overexpression of catalytically-active Akt or knockdown of glycogen synthase kinase-3 (GSK3)-β, a substrate for Akt, had little effect on Mcl-1 downregulation caused by S6K2 deficiency. Silencing of S6K2 increased the level of c-Jun N-terminal kinase (JNK) and knockdown of JNK1 increased basal Mcl-1 level and partly reversed the effect of S6K2 knockdown on Mcl-1 downregulation. JNK1 knockdown also had a modest effect in attenuating the increase in doxorubicin-induced apoptosis caused by S6K2 deficiency. These results suggest that S6K2 regulates apoptosis via multiple mechanisms, and involves both Akt and JNK.
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spelling pubmed-53543082017-04-06 Regulation of anti-apoptotic Bcl-2 family protein Mcl-1 by S6 kinase 2 Basu, Alakananda Sridharan, Savitha PLoS One Research Article The anti-apoptotic Bcl-2 family protein myeloid cell leukemia-1 (Mcl-1) plays an important role in breast cancer cell survival and chemoresistance. We have previously shown that knockdown of the 40S ribosomal protein S6 kinase-2 (S6K2), which acts downstream of the mechanistic target of rapamycin complex 1 (mTORC1), enhanced breast cancer cell death by apoptotic stimuli. The increase in cell death by S6K2 depletion was partly due to inactivation of Akt. In the present study, we investigated if S6K2 regulates Mcl-1, which acts downstream of Akt. Silencing of S6K2 but not S6K1 in T47D cells decreased Mcl-1 level, and potentiated apoptosis induced by TRAIL and doxorubicin. Knockdown of S6K2 also decreased the level of anti-apoptotic Bcl-xl. Depletion of the tumor suppressor protein PDCD4 (programmed cell death 4), which regulates translation of several anti-apoptotic proteins, reversed downregulation of Bcl-xl but not Mcl-1 and failed to reverse the effect of S6K2 knockdown on potentiation of doxorubicin-induced apoptosis. Downregulation of Mcl-1 by S6K2 knockdown was partly restored by the proteasome inhibitor MG132. Overexpression of catalytically-active Akt or knockdown of glycogen synthase kinase-3 (GSK3)-β, a substrate for Akt, had little effect on Mcl-1 downregulation caused by S6K2 deficiency. Silencing of S6K2 increased the level of c-Jun N-terminal kinase (JNK) and knockdown of JNK1 increased basal Mcl-1 level and partly reversed the effect of S6K2 knockdown on Mcl-1 downregulation. JNK1 knockdown also had a modest effect in attenuating the increase in doxorubicin-induced apoptosis caused by S6K2 deficiency. These results suggest that S6K2 regulates apoptosis via multiple mechanisms, and involves both Akt and JNK. Public Library of Science 2017-03-16 /pmc/articles/PMC5354308/ /pubmed/28301598 http://dx.doi.org/10.1371/journal.pone.0173854 Text en © 2017 Basu, Sridharan http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Basu, Alakananda
Sridharan, Savitha
Regulation of anti-apoptotic Bcl-2 family protein Mcl-1 by S6 kinase 2
title Regulation of anti-apoptotic Bcl-2 family protein Mcl-1 by S6 kinase 2
title_full Regulation of anti-apoptotic Bcl-2 family protein Mcl-1 by S6 kinase 2
title_fullStr Regulation of anti-apoptotic Bcl-2 family protein Mcl-1 by S6 kinase 2
title_full_unstemmed Regulation of anti-apoptotic Bcl-2 family protein Mcl-1 by S6 kinase 2
title_short Regulation of anti-apoptotic Bcl-2 family protein Mcl-1 by S6 kinase 2
title_sort regulation of anti-apoptotic bcl-2 family protein mcl-1 by s6 kinase 2
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354308/
https://www.ncbi.nlm.nih.gov/pubmed/28301598
http://dx.doi.org/10.1371/journal.pone.0173854
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