title: Autophagy gene expression profiling identifies a defective microtubule-associated protein light chain 3A mutant in cancer.
abstract: The cellular stress response autophagy has been implicated in various diseases including neuro-degeneration and cancer. The role of autophagy in cancer is not clearly understood and both tumour promoting and tumour suppressive effects of autophagy have been reported, which complicates the design of therapeutic strategies based on targeting the autophagy pathway. Here, we have systematically analyzed gene expression data for 47 autophagy genes for deletions, amplifications and mutations in various cancers. We found that several cancer types have frequent autophagy gene amplifications, whereas deletions are more frequent in prostate adenocarcinomas. Other cancer types such as glioblastoma and thyroid carcinoma show very few alterations in any of the 47 autophagy genes. Overall, individual autophagy core genes are altered at low frequency in cancer, suggesting that cancer cells require functional autophagy. Some autophagy genes show frequent single base mutations, such as members of the ULK family of protein kinases. Furthermore, we found hotspot mutations in the arginine-rich stretch in MAP1LC3A resulting in reduced cleavage of MAP1LC3A by ATG4B both in vitro and in vivo, suggesting a functional implication of this gene mutation in cancer development.
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom.
authors.forename: Joana R
authors.initials: JR
authors.lastname: Costa
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom.
authors.forename: Krisna
authors.initials: K
authors.lastname: Prak
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Aldous
authors.affiliation: Translational Research Office, University College London, London, United Kingdom.
authors.forename: Christina Anja
authors.initials: CA
authors.lastname: Gewinner
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom.
authors.forename: Robin
authors.initials: R
authors.lastname: Ketteler
mesh_terms: D001343:Autophagy / Q000235:genetics*; D000071183:Autophagy-Related Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D046228:Microarray Analysis; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D050505:Mutant Proteins / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*
chemical_list: D000071183:Autophagy-Related Proteins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D050505:Mutant Proteins
keywords: ATG4B; MAP1LC3A R70H; autophagy; gene expression; luciferase release assay