title: p57Kip2 is an unrecognized DNA damage response effector molecule that functions in tumor suppression and chemoresistance.
abstract: The DNA damage response (DDR) helps to maintain genome integrity, suppress tumorigenesis and mediate the radiotherapeutic and chemotherapeutic effects on cancer. Here we report that p57Kip2, a cyclin-dependent kinase (CDK) inhibitor implicated in the development of tumor-prone Beckwith-Wiedemann syndrome, is an effector molecule of the DNA-damage response. Genotoxic stress induces p57Kip2 expression via the bone morphogenetic protein-Smad1 and Atm-p38MAPK-Atf2 pathways in p53-proficient or -deficient cells and requires the Smad1-Atf2 complex that facilitates their recruitment to the p57Kip2 promoter. Elevated p57Kip2 induces G1/S phase cell cycle arrest but inhibits cell death in response to DNA damage and acts in parallel with p53 to suppress cell transformation and tumor formation. p57Kip2 is also upregulated in stage I and II clinical rectal tumor samples, likely due to genome instability of precancerous and/or early cancer cells. Targeting p57Kip2 in primary rectal cancer cells and tumor models resulted in increased sensitivity to doxorubicin, suggesting that p57Kip2 has a role in chemoresistance, which is consistent with its pro-survival function. These findings place p57Kip2 in DDR and uncover molecular mechanisms by which p57Kip2 suppresses tumorigenesis and causes chemoresistance.
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Jia
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Cong
authors.affiliation: The Institute of Molecular and Cell Biology, Singapore, Singapore.
authors.forename: J F L
authors.initials: JF
authors.lastname: Chua
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Xia
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Lin
authors.affiliation: South Texas Veterans Health Care System and Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Habib
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Ao
authors.affiliation: Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zuo
authors.affiliation: Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: C
authors.initials: C
authors.lastname: Fu
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: B
authors.initials: B
authors.lastname: Li
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000502:physiology*; D004249:DNA Damage / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D013312:Stress, Physiological / Q000235:genetics*
chemical_list: D050761:Cyclin-Dependent Kinase Inhibitor p57