CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells

Cancer stem cells promote neoplastic growth, in part by deregulating asymmetric cell division and enhancing self-renewal. To uncover mechanisms and potential therapeutic targets in glioma stem cell (GSC) self-renewal, we performed a genetic suppressor screen for kinases to reverse the tumor phenotyp...

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Autores principales: Mukherjee, Subhas, Tucker-Burden, Carol, Kaissi, Emily, Newsam, Austin, Duggireddy, Hithardhi, Chau, Monica, Zhang, Changming, Diwedi, Bhakti, Rupji, Manali, Seby, Sandra, Kowalski, Jeanne, Kong, Jun, Read, Renee, Brat, Daniel J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987254/
https://www.ncbi.nlm.nih.gov/pubmed/29742423
http://dx.doi.org/10.1016/j.celrep.2018.04.016
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author Mukherjee, Subhas
Tucker-Burden, Carol
Kaissi, Emily
Newsam, Austin
Duggireddy, Hithardhi
Chau, Monica
Zhang, Changming
Diwedi, Bhakti
Rupji, Manali
Seby, Sandra
Kowalski, Jeanne
Kong, Jun
Read, Renee
Brat, Daniel J.
author_facet Mukherjee, Subhas
Tucker-Burden, Carol
Kaissi, Emily
Newsam, Austin
Duggireddy, Hithardhi
Chau, Monica
Zhang, Changming
Diwedi, Bhakti
Rupji, Manali
Seby, Sandra
Kowalski, Jeanne
Kong, Jun
Read, Renee
Brat, Daniel J.
author_sort Mukherjee, Subhas
collection PubMed
description Cancer stem cells promote neoplastic growth, in part by deregulating asymmetric cell division and enhancing self-renewal. To uncover mechanisms and potential therapeutic targets in glioma stem cell (GSC) self-renewal, we performed a genetic suppressor screen for kinases to reverse the tumor phenotype of our Drosophila brain tumor model and identified dCdk5 as a critical regulator. CDK5, the human ortholog of dCdk5 (79% identity), is aberrantly activated in GBMs and tightly aligned with both chromosome 7 gains and stem cell markers affecting tumor-propagation. Our investigation revealed that pharmaceutical inhibition of CDK5 prevents GSC self-renewal in vitro and in xenografted tumors, at least partially by suppressing CREB1 activation independently of PKA/cAMP. Finally, our TCGA GBM data analysis revealed that CDK5, stem cell, and asymmetric cell division markers segregate within non-mesenchymal patient clusters, which may indicate preferential dependence on CDK5 signaling and sensitivity to its inhibition in this group.
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spelling pubmed-59872542018-06-05 CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells Mukherjee, Subhas Tucker-Burden, Carol Kaissi, Emily Newsam, Austin Duggireddy, Hithardhi Chau, Monica Zhang, Changming Diwedi, Bhakti Rupji, Manali Seby, Sandra Kowalski, Jeanne Kong, Jun Read, Renee Brat, Daniel J. Cell Rep Article Cancer stem cells promote neoplastic growth, in part by deregulating asymmetric cell division and enhancing self-renewal. To uncover mechanisms and potential therapeutic targets in glioma stem cell (GSC) self-renewal, we performed a genetic suppressor screen for kinases to reverse the tumor phenotype of our Drosophila brain tumor model and identified dCdk5 as a critical regulator. CDK5, the human ortholog of dCdk5 (79% identity), is aberrantly activated in GBMs and tightly aligned with both chromosome 7 gains and stem cell markers affecting tumor-propagation. Our investigation revealed that pharmaceutical inhibition of CDK5 prevents GSC self-renewal in vitro and in xenografted tumors, at least partially by suppressing CREB1 activation independently of PKA/cAMP. Finally, our TCGA GBM data analysis revealed that CDK5, stem cell, and asymmetric cell division markers segregate within non-mesenchymal patient clusters, which may indicate preferential dependence on CDK5 signaling and sensitivity to its inhibition in this group. 2018-05-08 /pmc/articles/PMC5987254/ /pubmed/29742423 http://dx.doi.org/10.1016/j.celrep.2018.04.016 Text en http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Mukherjee, Subhas
Tucker-Burden, Carol
Kaissi, Emily
Newsam, Austin
Duggireddy, Hithardhi
Chau, Monica
Zhang, Changming
Diwedi, Bhakti
Rupji, Manali
Seby, Sandra
Kowalski, Jeanne
Kong, Jun
Read, Renee
Brat, Daniel J.
CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells
title CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells
title_full CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells
title_fullStr CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells
title_full_unstemmed CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells
title_short CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells
title_sort cdk5 inhibition resolves pka/camp-independent activation of creb1 signaling in glioma stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987254/
https://www.ncbi.nlm.nih.gov/pubmed/29742423
http://dx.doi.org/10.1016/j.celrep.2018.04.016
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