title: P53 deficiency-induced Smad1 upregulation suppresses tumorigenesis and causes chemoresistance in colorectal cancers.
abstract: The DNA damage response helps to maintain genome integrity, suppress tumorigenesis, and mediate the effects of radiotherapy and chemotherapy. Our previous studies have shown that Smad1 is upregulated and activated by Atm in DNA damage response, which can further bind to p53 and promote p53 stabilization. Here we report another aspect of the interplay between p53 and Smad1. Comparison of rectal tumor against paired paraneoplastic specimens and analysis of >500 colorectal tumors revealed that Smad1 was upregulated in tumor samples, which was attributable to p53 defects. Using MEFs as a model, we found that knockdown of the elevated Smad1 in p53(-/-) MEFs promoted cell proliferation, E1A/Ras-induced cell transformation, and tumorigenesis. Mechanistic studies suggest that elevated Smad1 and momentary activation inhibit cell proliferation by upregulating p57Kip2 and enhancing Atm-Chk2 activation. Surprisingly, elevated Smad1 appears to have a negative effect on chemotherapy, as colorectal tumors, primary cancer cells, and cell lines with Smad1 knockdown all showed an increase in chemosensitivity, which could be attributable to elevated p57Kip2. These findings underscore the significance of Smad1-p53 interaction in tumor suppression and reveal an unexpected role for Smad1 in chemoresistance of colorectal cancers.
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Xinsen
authors.initials: X
authors.lastname: Ruan
authors.affiliation: Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Zuo
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Jia
authors.affiliation: Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673, Singapore.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chau
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Jinlin
authors.initials: J
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200032, China.
authors.forename: Junping
authors.initials: J
authors.lastname: Ao
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Xuechun
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 200240, China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Samy L
authors.initials: SL
authors.lastname: Habib
authors.affiliation: Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China libj@sjtu.edu.cn fugang416@126.com.
authors.forename: Chuangang
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 200240, China libj@sjtu.edu.cn fugang416@126.com.
authors.forename: Baojie
authors.initials: B
authors.lastname: Li
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D012004:Rectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D015854:Up-Regulation
chemical_list: D000903:Antibiotics, Antineoplastic; C497399:SMAD1 protein, human; D051898:Smad1 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human
keywords: Smad1; chemoresistance; colorectal cancer; p53; p57Kip2