title: RhoGAPs attenuate cell proliferation by direct interaction with p53 tetramerization domain.
abstract: Many Rho GTPase activation proteins (RhoGAPs) are deleted or downregulated in cancers, but the functional consequences are still unclear. Here, we show that the RhoGAP ArhGAP11A induces cell-cycle arrest and apoptosis by binding to the tumor suppressor p53. The RhoGAP domain of ArhGAP11A binds to the tetramerization domain of p53, but not to its family members p63 or p73. The interaction stabilizes the tetrameric conformation of p53 and enhances its DNA-binding activity, thereby inducing cell-cycle arrest and apoptosis. Upon DNA damage stress, ArhGAP11A accumulates in the nucleus and interacts with p53, whereas knockdown of ArhGAP11A partially blocks p53 transcriptional activity. These findings explain why RhoGAPs are frequently deleted in cancers and suggest that the RhoGAP family sits at the crossroads between the cell-migration and proliferation pathways.
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Institute for Digestive Diseases, Shanghai Jiao-Tong University School of Medicine, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, 145 Middle Shandong Road, Shanghai 200001, China. xujieletter@gmail.com
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhou
authors.forename: Jilin
authors.initials: J
authors.lastname: Wang
authors.forename: Zhaoli
authors.initials: Z
authors.lastname: Li
authors.forename: Xuan
authors.initials: X
authors.lastname: Kong
authors.forename: Jin
authors.initials: J
authors.lastname: Qian
authors.forename: Ye
authors.initials: Y
authors.lastname: Hu
authors.forename: Jing-Yuan
authors.initials: JY
authors.lastname: Fang
mesh_terms: D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C473316:ARHGAP15 protein, human; D020690:GTPase-Activating Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C085379:rho GTPase-activating protein; D004247:DNA