Kinase-Mediated Regulation of 40S Ribosome Assembly in Human Breast Cancer
Abstract
The BCRP Breakthrough DOD_W81XWH-15-BCRP-BREAKTHROUGH-FL12) studies of the laboratories of Drs. Katrin Karbstein (Initiating Principal Investigator [PI], Scripps) and John Cleveland (Collaborating/Partnering 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 serine/threonine casein kinase-1delta (CK1delta)phosphorylates 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2017
- Accession Number
- AD1036025
Entities
People
- Katrin Karbstein
Organizations
- Scripps Research