A MYC-PROTEIN KINASE A SIGNALING LOOP REGULATES MYC IN PROSTATE CANCER CELLS

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dc.contributor.advisorBieberich, Charles J.
dc.contributor.authorPADMANABHAN, ACHUTH
dc.contributor.departmentBiological Sciences
dc.contributor.programBiological Sciences
dc.date.accessioned2015-10-14T03:12:38Z
dc.date.available2015-10-14T03:12:38Z
dc.date.issued2012-01-01
dc.description.abstractMYC is frequently overexpressed in many human malignancies including prostate cancer. MYC accumulation is tightly regulated through transcriptional and post-translational mechanisms. Here, we demonstrate that a complex MYC/Protein Kinase A (PKA) signaling loop functions in prostate cancer cells. We show that MYC up-regulates Protein Kinase A Catalytic subunit � (PKAC�) transcription in human prostate cancer cells and mouse prostate cancers. We further demonstrate that PKA positively regulates MYC by phosphorylating Ser279, thereby priming phosphorylation by Polo-like kinase 1 at Ser281 and protecting MYC from degradation. Consistent with this, brief pharmacologic pan-PKA inhibition diminishes MYC level. Paradoxically however, prolonged Protein Kinase A Catalytic subunit ? (PKAC?), but not PKAC�, knockdown increases MYC mRNA and protein levels, linking transcriptional repression of MYC with PKAC? activity, and revealing distinct functional roles among PKA catalytic isoforms in MYC regulation. We demonstrate that this effect stems from differential substrate selectivity among PKA isoforms, providing a mechanistic understanding of differential MYC regulation by PKA. Our observations establish PKA as a viable therapeutic target in MYC-overexpressing cancers, but highlight the risk of global PKA inhibition, underscoring the need to develop advanced inhibition strategies to disrupt specific kinase/substrate interactions.
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dc.identifierdoi:10.13016/M2KD5Z
dc.identifier.other10610
dc.identifier.urihttp://hdl.handle.net/11603/1023
dc.languageen
dc.relation.isAvailableAtThe University of Maryland, Baltimore County (UMBC)
dc.relation.ispartofUMBC Theses and Dissertations Collection
dc.relation.ispartofUMBC Graduate School Collection
dc.relation.ispartofUMBC Student Collection
dc.relation.ispartofUMBC Biological Sciences Department Collection
dc.rightsThis item may be protected under Title 17 of the U.S. Copyright Law. It is made available by UMBC for non-commercial research and education. For permission to publish or reproduce, please see http://aok.lib.umbc.edu/specoll/repro.php or contact Special Collections at speccoll(at)umbc.edu.
dc.sourcePADMANABHAN_umbc_0434D_10610.pdf
dc.subjectMYC
dc.subjectPhosphorylation
dc.subjectPolo-like Kinase 1
dc.subjectProstate Cancer
dc.subjectProtein Kinase A
dc.subjectProtein Kinases
dc.titleA MYC-PROTEIN KINASE A SIGNALING LOOP REGULATES MYC IN PROSTATE CANCER CELLS
dc.typeText
dcterms.accessRightsAccess limited to the UMBC community. Item may possibly be obtained via Interlibrary Loan through a local library, pending author/copyright holder's permission.

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