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Kinase-Mediated Regulation of 40S Ribosome Assembly in Human Breast Cancer

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Technical Report,01 Feb 2016,31 Jan 2017

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The Scripps Research Institute Jupiter United States

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The BCRP Breakthrough DODW81XWH-15-BCRP-BREAKTHROUGH-FL12 studies of the laboratories of Drs. Katrin Karbstein Initiating Principal Investigator PI, Scripps and John Cleveland CollaboratingPartnering PI, Moffitt Cancer Center seek to validate 40S ribosome assembly as a therapeutic target for triple negative breast cancer TNBC. Specifically, we have shown that the serinethreonine casein kinase-1delta CK1deltaphosphorylates the 40S ribosome assembly factor Ltv1, and that selective knockdown or silencing of CK1delta, or forced expression of Ltv1 mutant that can not be phosphorylated by CK1delta, blocks ribosome assembly and compromises the growth and survival of TNBC. Further, we have shown that forced overexpression of a phospho-mimetic Ltv1 mutant i.e., constitutively active Ltv1 can override the deleterious effects of CK1delta inhibitors or CK1delta silencing on ribosome assembly. Using genetic approaches, we will define roles of the CK1delta-to-Ltv1 circuit in TNBC growth and survival, and will assess if TNBC regression triggered by CK1delta inhibition or loss disables in ribosome assembly via effects on Ltv1. We have also developed TNBC tumor cells that are resistant to CK1 inhibitors, and will assess if this resistance involves gain-of-function mutations in Ltv1, and if resistance can be overcome with drugs that direct destruction of ribosome assembly intermediates via the autophagy pathway.

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