Novel Role of Merlin Tumor Suppressor in Autophagy and its Implication in Treating NF2-Associated Tumors
Abstract
The overall goal of the proposed research is to elucidate the novel function of Merlin in autophagy, a cellular catabolic pathway implicated in tumorigenesis, and to control the Merlin-mediated tumorigenesis by modulating cellular autophagy. We have recently demonstrated that Merlin binds an autophagy regulator protein, and that loss of Merlin leads to attenuated autophagy as well as enhanced hypoxia or metabolic stress in the three-dimensional (3D) microenvironment in culture, a condition known to accelerate tumor formation. Moreover, this elevated level of metabolic stress is suppressed by rapamycin, an autophagy inducer. Therefore, we hypothesize that Merlin normally suppresses tumorigenesis in part by activating autophagy, and that this new role of Merlin in autophagy could be a target for therapeutic intervention for NF2-associated tumors. To test this hypothesis, we precisely evaluated the interaction of Merlin with autophagy-related proteins, including LC3, and Unc51.1/Atg1. This analysis revealed that the interaction of Merlin with LC3 and Unc51/Atg1 is significantly upregulated upon autophagy induction. In addition, we have successfully developed the cell culture system to evaluate autophagy-inducing ability of Merlin mutants. This analysis revealed that at least one point mutant Merlin/K79E specifically abolished the autophagic activity. We will continue to advance our study to delineate the role of Merlin-mediated autophagy in the regulation of tumorigenesis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2012
- Accession Number
- ADA563285
Entities
People
- Donald Jhung Jr.
- Toshifumi Tomoda
- Yuki Hirota