p53 deficiency-induced Smad1 upregulation suppresses tumorigenesis and causes chemoresistance in colorectal cancers

作     者：Xinsen Ruan Qiao Zuo Hao Jia Jenny Chau Jinlin Lin Junping Ao Xuechun Xia Huijuan Liu Samy LHabib Chuangang Fu Baojie Li 

作者机构：Bio-X InstitutesKey Laboratory for the Genetics of Developmental and Neuropsychiatric DisordersMinistry of EducationShanghai Jiao Tong UniversityShanghai 200240China Department of Colorectal SurgeryChanghai HospitalSecond Military Medical UniversityShanghai 200433China Institute of Molecular and Cell BiologyProteos61 Biopolis DriveSingapore 138673Singapore State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong UniversitySchool of MedicineShanghai 200032China Department of Cellular and Structural BiologyUniversity of Texas Health Science Center at San AntonioSan AntonioTX 78229USA 

出 版 物：《分子细胞生物学报:英文版》 (Journal of Molecular Cell Biology)

年 卷 期：2015年第7卷第2期

页      面：105-118页

核心收录：

学科分类：0710[理学-生物学] 0831[工学-生物医学工程（可授工学、理学、医学学位）] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100214[医学-肿瘤学] 10[医学] 

基　　金：This work was supported by grants from the National Natural Science Foundation of China(81130039,31300684,and 81421061) the National Key Basic Research Program of China(2012CB966901 and 2014CB942900) Program of Shanghai Subject Chief Scientist(13XD1401900). 

主　　题：Smad1 p53 p57Kip2 chemoresistance colorectal cancer 

摘      要：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.Herewe report another aspect of the interplay between p53 and Smad1.Comparison of rectal tumor against paired paraneoplastic specimens and analysis of500 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 p532/2 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.