title: Regulation of Rad17 protein turnover unveils an impact of Rad17-APC cascade in breast carcinogenesis and treatment.
abstract: Aberrant regulation of DNA damage checkpoint function leads to genome instability that in turn can predispose cellular tissues to become cancerous. Previous works from us and others demonstrated the role of Rad17 in either activation or termination of DNA damage checkpoint function. In the current study, we have revealed the unexpected accumulation of Rad17 in various types of breast cancer cell lines as well as human breast cancer tissues. We observed that Rad17 protein turnover rate in breast epithelial cells is much faster than in breast cancer cells, where the turnover of Rad17 is regulated by the Cdh1/APC pathway. We further observed that Rad17-mediated checkpoint function is modulated by proteolysis. Stabilization of Rad17 disrupts cellular response to chemotherapeutic drug-induced DNA damage and enhances cellular transformation. In addition, manipulation of Rad17 by RNA interference or stabilization of Rad17 significantly sensitize breast cancer cell to various chemotherapeutic drugs. Our present results indicate the manipulation of Rad17 proteolysis could be a valuable approach to sensitize breast cancer cell to the chemotherapeutic treatment despite of the critical role in governing DNA damage response and cellular recovery from genotoxic stress.
authors: Department of Cell Biology, University of Pittsburgh School of Medicine and Hillman Cancer Center, Pittsburgh, Pennsylvania 15213, USA.
authors: Zhuan
authors: Z
authors: Zhou
authors: Chao
authors: C
authors: Jing
authors: Liyong
authors: L
authors: Zhang
authors: Fujita
authors: F
authors: Takeo
authors: Hyun
authors: H
authors: Kim
authors: Yi
authors: Y
authors: Huang
authors: Zhihua
authors: Z
authors: Liu
authors: Yong
authors: Y
authors: Wan
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D061986:MCF-7 Cells; D008957:Models, Genetic; D011485:Protein Binding / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D034622:RNA Interference; D015398:Signal Transduction; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C513384:CDH1 protein, human; D015820:Cadherins; D018797:Cell Cycle Proteins; C113575:Rad17 protein, human; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D002945:Cisplatin
keywords: APC; Carcinogenesis; Chromosomes/non-histone Chromosomal Proteins; DNA Binding Protein; Genome Instability; Protein Dynamics; Protein Stability; Protein Turnover; Rad17
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