title: GADD45A inhibits autophagy by regulating the interaction between BECN1 and PIK3C3.
abstract: GADD45A is a TP53-regulated and DNA damage-inducible tumor suppressor protein, which regulates cell cycle arrest, apoptosis, and DNA repair, and inhibits tumor growth and angiogenesis. However, the function of GADD45A in autophagy remains unknown. In this report, we demonstrate that GADD45A plays an important role in regulating the process of autophagy. GADD45A is able to decrease LC3-II expression and numbers of autophagosomes in mouse tissues and different cancer cell lines. Using bafilomycin A1 treatment, we have observed that GADD45A regulates autophagosome initiation. Likely, GADD45A inhibition of autophagy is through its influence on the interaction between BECN1 and PIK3C3. Immunoprecipitation and GST affinity isolation assays exhibit that GADD45A directly interacts with BECN1, and in turn dissociates the BECN1-PIK3C3 complex. Furthermore, we have mapped the 71 to 81 amino acids of the GADD45A protein that are necessary for the GADD45A interaction with BECN1. Knockdown of BECN1 can abolish autophagy alterations induced by GADD45A. Taken together, these findings provide the novel evidence that GADD45A inhibits autophagy via impairing the BECN1-PIK3C3 complex formation.
authors.affiliation: a State Key Laboratory of Molecular Oncology; Cancer Institute and Hospital; Chinese Academy of Medical Sciences & Peking Union Medical College ; Beijing , China.|b CAS Key Laboratory of RNA Biology; Institute of Biophysics; Chinese Academy of Sciences ; Beijing , China.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: a State Key Laboratory of Molecular Oncology; Cancer Institute and Hospital; Chinese Academy of Medical Sciences & Peking Union Medical College ; Beijing , China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Zhang
authors.affiliation: a State Key Laboratory of Molecular Oncology; Cancer Institute and Hospital; Chinese Academy of Medical Sciences & Peking Union Medical College ; Beijing , China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: a State Key Laboratory of Molecular Oncology; Cancer Institute and Hospital; Chinese Academy of Medical Sciences & Peking Union Medical College ; Beijing , China.
authors.forename: Ming
authors.initials: M
authors.lastname: Fu
authors.affiliation: b CAS Key Laboratory of RNA Biology; Institute of Biophysics; Chinese Academy of Sciences ; Beijing , China.
authors.forename: Runsheng
authors.initials: R
authors.lastname: Chen
authors.affiliation: a State Key Laboratory of Molecular Oncology; Cancer Institute and Hospital; Chinese Academy of Medical Sciences & Peking Union Medical College ; Beijing , China.|c Collaborative Innovation Center For Biotherapy; West China Hospital; Sichuan University ; Sichuan , China.
authors.forename: Qimin
authors.initials: Q
authors.lastname: Zhan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D058546:Class III Phosphatidylinositol 3-Kinases; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D000097642:GADD45 Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D018797:Cell Cycle Proteins; D058546:Class III Phosphatidylinositol 3-Kinases; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; C115010:Becn1 protein, mouse; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins; C000611846:PIK3C3 protein, mouse
keywords: BECN1; GADD45A; PIK3C3; autophagy; tumor