Phosphorylation status of Ascl1 regulates neuroblast self-renewal and differentiation

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NCI	CANCER-29

Authors

• LA Wylie
• K Cheng
• CJ Thiele
• A Philpott

Abstract

Neuroblastoma (NB) is a tumor of improper development of the noradrenergic neurons. Retinoic acid RA) has been shown to differentiate NB in vitro and provide benefit to patients. Achaete-scute homolog 1 (Ascl1) is a proneural transcription factor that is both necessary and sufficient for neural differentiation of noradrenergic neurons. However, Ascl1 is highly expressed and associated with poor prognosis in NB. Based on previous work in the developing sympathetic nervous system, we hypothesized that phosphorylation status of Ascl1, by cyclin-dependent kinases (CDK), critically regulates its ability to induce neural differentiation. Initial studies show that Ascl1 is phosphorylated in SY5Y and SKNAS neuroblastoma cell lines. Overexpression of Ascl1 wild type activates downstream targets associated with cell cycle promotion, while overexpression of a phosphomutant, lacking phosphorylation sites, activates downstream targets associated with cell cycle exit and differentiation. Treatment with CDK inhibitors and RA causes increased differentiation in RA-susceptible cell lines, KCNR and SY5Y, and induces differentiation in RA-resistant SKNAS cells. We propose a model by where Cdks maintain Ascl1 in a phosphorylated state preventing neural differentiation. This provides a mechanistic tie between cell cycle exit and differentiation sugesting cell cycle inhibition combined with RA will be clinically active.

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