Peroxisomes are autonomously replicating organelles, and a major source of ROS generation in the cell. In the previous funding period, we made two major discoveries that form the basis for this competitive renewal: 1) the DNA repair kinase ATM moonlights in the cytoplasm where it signals to the TSC tumor suppressor to repress mTORC1 signaling in response to ROS and 2) the TSC signaling node (TSC1, TSC2 and Rheb) is resident at the peroxisome, where it is activated in response to ROS generation by this organelle. These findings have led us to hypothesize that the peroxisome is an import site for functional interaction between the TSC and ATM tumor suppressors, and that this interaction plays a key role in maintaining peroxisomal homeostasis by regulating selective autophagy of peroxisome (pexophagy). We hypothesize that ATM localizes to the peroxisome, where it is activated by peroxisomal ROS and signals downstream to TSC2 to suppress mTORC1 (Aim 1). In addition to the TSC tumor suppressor, our Preliminary Data suggest the ATM kinase also phosphorylates PEX5 (and perhaps other) proteins resident at the peroxisome (Aim 2), targeting them for ubiquitination and recognition by autophagy adaptor proteins to recruit the autophagosome to the peroxisome and mediate pexophagy (Aim 3). Together, the studies proposed in this application would be the first to demonstrate ATM signaling at the peroxisome, and to define new functional site for interaction of the ATM and TSC tumor suppressors, with important implications for understanding the role of these tumor suppressors in peroxisome homeostasis and maintenance of cellular redox balance.

Public Health Relevance

Peroxisomes are important organelles that serve several key cellular functions, but also carry a tremendous liability for the cell, as they generate reactive oxygen species (ROS) that can damage and even kill cells. It has remained a mystery as to how cells maintain just the right number of these necessary but dangerous organelles. In this grant, we propose to solve this mystery with our hypothesis that cells use ROS generated by peroxisomes as a rheostat to know when peroxisome number is too high to remove these organelles and maintain peroxisome homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA143811-10
Application #
9530548
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Espey, Michael G
Project Start
2010-01-25
Project End
2019-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Hasanov, E; Chen, G; Chowdhury, P et al. (2017) Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL. Oncogene 36:3450-3463
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Tripathi, Durga Nand; Walker, Cheryl Lyn (2016) The peroxisome as a cell signaling organelle. Curr Opin Cell Biol 39:109-12
Zhou, L; Liu, X-D; Sun, M et al. (2016) Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene 35:2687-97
Tripathi, Durga Nand; Zhang, Jiangwei; Jing, Ji et al. (2016) A new role for ATM in selective autophagy of peroxisomes (pexophagy). Autophagy 12:711-2
Ho, T H; Park, I Y; Zhao, H et al. (2016) High-resolution profiling of histone h3 lysine 36 trimethylation in metastatic renal cell carcinoma. Oncogene 35:1565-74
Zhang, Jiangwei; Tripathi, Durga Nand; Jing, Ji et al. (2015) ATM functions at the peroxisome to induce pexophagy in response to ROS. Nat Cell Biol 17:1259-1269
Liu, X-D; Yao, J; Tripathi, D N et al. (2015) Autophagy mediates HIF2? degradation and suppresses renal tumorigenesis. Oncogene 34:2450-60
Jing, Ji; He, Lian; Sun, Aomin et al. (2015) Proteomic mapping of ER-PM junctions identifies STIMATE as a regulator of Ca²? influx. Nat Cell Biol 17:1339-47
Dere, Ruhee; Perkins, Ashley Lyn; Bawa-Khalfe, Tasneem et al. (2015) ?-catenin links von Hippel-Lindau to aurora kinase A and loss of primary cilia in renal cell carcinoma. J Am Soc Nephrol 26:553-64

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