Accession Number:

ADA604191

Title:

Defining the Role of Autophagy Kinase ULK1 Signaling in Therapeutic Response of Tuberous Sclerosis Complex to mTOR Inhibitors

Descriptive Note:

Annual rept. 1 Apr 2013-31 Mar 2014

Corporate Author:

SALK INST FOR BIOLOGICAL STUDIES LA JOLLA CA

Personal Author(s):

• Shaw, Reuben J.

Report Date:

2014-04-01

Pagination or Media Count:

14.0

Abstract:

The Tuberous Sclerosis Complex tumor suppressors are known to be critical negative regulators of the mTORC1 kinase complex that controls cell growth and autophagy. Our laboratory and others have recently decoded a major conserved route that mTORC1 uses to control autophagy. These studies demonstrate that mTORC1 inactivates another kinase complex composed of the autophagy kinase ULK1 and its associated subunits. One prediction of these findings is that in cells and tumors with TSC mutations and hyperactive mTOR, the ULK1 complex and the process of autophagy will be suppressed. There were two major aims for this funding period 1 to better define phosphorylation sites newly identified ULK1 substrates to be used as biomarkers of mTOR inhibition, and 2 to determine whether novel small molecule inhibitors of ULK1 convert the cytostatic effects of mTOR inhibitors into cytotoxic effects when used in combination.

Descriptors:

• *GENETIC DISEASES
• *NERVOUS SYSTEM DISEASES
• *SKIN DISEASES
• CYTOTOXINS
• MUTATIONS
• NEOPLASMS
• PHOSPHORYLATION

Subject Categories:

• Anatomy and Physiology
• Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE