Mitochondria supply energy for cellular function while their dysfunction causes cell death. Endoplasmic reticulum (ER) mediates protein synthesis and folding and its dysfunction causes ER stress and protein aggregation. Autophagy is activated to clean up defective mitochondria and protein aggregates (aggresomes) through lysosomes to maintain mitochondrial homeostasis and relieve ER stress. Autophagic dysfunction induces oxidative stress that causes DNA double strand breaks and the generation of aneuploidy cells leading to cancers. We discovered that C19ORF5 regulates general autophagy and mitotic mitophagy in collaboration with tumor suppressor RASSF1A-mediated microtubular dynamics and overall autophagic activity via Bcl-2/XL protein-controlled canonical and noncanonical autophagic pathways. We predict that C19ORF5 inhibits the generation of aneuploidy to prevent cancer at its origin and impedes further karyotype evolution that underlies cancer's variability and relapse after therapy. To test the hypothesis, specific aims are designed to characterize (1) the mechanism by which C19ORF5 regulates autophagy, and (2) the mechanism by which C19ORF5 suppresses tumorigenesis through autophagic regulation. The experimental approach will use C19ORF5 knockout mice carrying a transgenic autophagic marker GFP-LC3 and their primary hepatocyte cultures as models for biochemical, cell biological and cancer biological studies. The ultimate goal is to understand the general mechanism of tumor suppression and develop strategies to prevent cancers at their origin and terminate cancer relapse after therapy in general using the hepatoma as a prototype.

Public Health Relevance

It is estimated that about half of ageing-related human diseases are caused by accumulation of cellular garbage due to dysfunction in mechanisms for cleaning up mis-folded/aggregated proteins and worn-out dysfunctional organelles. Autophagy, mitophagy when applied to mitochondria, maintains a healthy population of mitochondria and eliminates the toxic macromolecular waste so that oxidative stress-induced genomic instability is prevented. C19ORF5 regulates autophagy in general and mitophagy in particular and prevents tumorigenesis. The new knowledge will eventually lead to develop strategies to terminate cancer at its earliest origin, sensitize human cancers to radiation treatment and chemotherapy, and prevent tumor re-growth and disease recurrence.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Salnikow, Konstantin
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Texas A&M University
Schools of Medicine
College Station
United States
Zip Code
Shi, Ming; Zhang, Yifan; Liu, Leyuan et al. (2016) MAP1S Protein Regulates the Phagocytosis of Bacteria and Toll-like Receptor (TLR) Signaling. J Biol Chem 291:1243-50
Xu, Guibin; Jiang, Yaodong; Xiao, Yuansong et al. (2016) Fast clearance of lipid droplets through MAP1S-activated autophagy suppresses clear cell renal cell carcinomas and promotes patient survival. Oncotarget 7:6255-65
Huang, Hai; Du, Tao; Xu, Guibin et al. (2016) Matrine suppresses invasion of castration-resistant prostate cancer cells by downregulating MMP-2/9 via NF-κB signaling pathway. Int J Oncol :
Li, Qi; Lai, Yiming; Wang, Chengbin et al. (2016) Matrine inhibits the proliferation, invasion and migration of castration-resistant prostate cancer cells through regulation of the NF-κB signaling pathway. Oncol Rep 35:375-81
Xu, Guibin; Yue, Fei; Huang, Hai et al. (2016) Defects in MAP1S-mediated autophagy turnover of fibronectin cause renal fibrosis. Aging (Albany NY) 8:977-85
Li, Wenjiao; Zou, Jing; Yue, Fei et al. (2016) Defects in MAP1S-mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed. Aging Cell 15:370-9
(2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Jiang, Xianhan; Zhong, Weide; Huang, Hai et al. (2015) Autophagy defects suggested by low levels of autophagy activator MAP1S and high levels of autophagy inhibitor LRPPRC predict poor prognosis of prostate cancer patients. Mol Carcinog 54:1194-204
Chen, Qi; Yue, Fei; Li, Wenjiao et al. (2015) Potassium Bisperoxo(1,10-phenanthroline)oxovanadate (bpV(phen)) Induces Apoptosis and Pyroptosis and Disrupts the P62-HDAC6 Protein Interaction to Suppress the Acetylated Microtubule-dependent Degradation of Autophagosomes. J Biol Chem 290:26051-8
Zou, Jing; Li, Wenjiao; Misra, Anisha et al. (2015) The viral restriction factor tetherin prevents leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) from association with beclin 1 and B-cell CLL/lymphoma 2 (Bcl-2) and enhances autophagy and mitophagy. J Biol Chem 290:7269-79

Showing the most recent 10 out of 24 publications