Accession Number:

ADA608945

Title:

Novel Role of Merlin Tumor Suppressor in Autophagy and its Implication in Treating NF2-Associated Tumors

Descriptive Note:

Annual rept. 1 Apr 2013-31 Mar 2014

Corporate Author:

CITY OF HOPE BECKMAN RESEARCH INST DUARTE CA

Report Date:

2014-04-01

Pagination or Media Count:

12.0

Abstract:

We have recently demonstrated that Merlin regulates the induction of autophagy, a cellular catabolic pathway implicated in the maintenance of cellular homeostasis. Deregulated autophagy is linked to a number of human disease conditions, including tumorigenesis. During this grant award period, we demonstrated that Merlin interacts with several autophagy-related proteins i.e., LC3, Ulk1, and dynein, and LC3-Merlin-dynein complex formation was dependent on Ulk1 kinase activity. In addition, cell biological analyses showed that autophagy induction is attenuated in cells that express MerlinK79E, a point mutation found in NF2 patients. Merlin K79E abolished the affinity to LC3. Additional Merlin mutants also showed attenuated affinity to LC3 and reduced ability to induce autophagy. Finally, we established the 3D culture system to evaluate the extent of metabolic stress caused by loss of Merlin function. We showed that loss of Merlin leads to attenuated autophagy and consequent elevation of metabolic stress, a condition known to accelerate tumor formation in vivo. This metabolic stress can be suppressed by an autophagy inducer rapamycin. These results suggest that autophagy induction can be an alternative avenue for treating NF2.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE