title: The RASSF6 tumor suppressor protein regulates apoptosis and the cell cycle via MDM2 protein and p53 protein.
abstract: Ras association domain family (RASSF) 6 is a member of the C-terminal RASSF proteins such as RASSF1A and RASSF3. RASSF6 is involved in apoptosis in various cells under miscellaneous conditions, but it remains to be clarified how RASSF6 exerts tumor-suppressive roles. We reported previously that RASSF3 facilitates the degradation of MDM2, a major E3 ligase of p53, and stabilizes p53 to function as a tumor suppressor. In this study, we demonstrate that RASSF6 overexpression induces G1/S arrest in p53-positive cells. Its depletion prevents UV- and VP-16-induced apoptosis and G1/S arrest in HCT116 and U2OS cells. RASSF6-induced apoptosis partially depends on p53. RASSF6 binds MDM2 and facilitates its ubiquitination. RASSF6 depletion blocks the increase of p53 in response to UV exposure and up-regulation of p53 target genes. RASSF6 depletion delays DNA repair in UV- and VP-16-treated cells and increases polyploid cells after VP-16 treatment. These findings indicate that RASSF6 stabilizes p53, regulates apoptosis and the cell cycle, and functions as a tumor suppressor. Together with the previous reports regarding RASSF1A and RASSF3, the stabilization of p53 may be the common function of the C-terminal RASSF proteins.
authors.affiliation: From the Department of Medical Biochemistry and.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Iwasa
authors.affiliation: From the Department of Medical Biochemistry and; Department of Neurosurgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan and.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kudo
authors.affiliation: From the Department of Medical Biochemistry and; the Department of Psychotherapy, The Fourth People's Hospital of Urumqi, Urumqi 830000, China.
authors.forename: Sainawaer
authors.initials: S
authors.lastname: Maimaiti
authors.affiliation: From the Department of Medical Biochemistry and.
authors.forename: Mitsunobu
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: From the Department of Medical Biochemistry and.
authors.forename: Junichi
authors.initials: J
authors.lastname: Maruyama
authors.affiliation: From the Department of Medical Biochemistry and.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: From the Department of Medical Biochemistry and. Electronic address: yuhammch@tmd.ac.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hata
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005047:Etoposide / Q000494:pharmacology; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C519911:RASSF6 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D020559:Monomeric GTP-Binding Proteins
keywords: Apoptosis; Checkpoint Control; DNA Damage; Hippo Pathway; RASSF; Tumor Suppressor Gene; p53