CSR1 induces cell death through inactivation of CPSF3

• Published in: Oncogene Vol. 28; no. 1; pp. 41 - 51
• Main Authors: Zhu, Z-H, Yu, Y P, Shi, Y-K, Nelson, J B, Luo, J-H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.01.2009; Nature Publishing Group
• Subjects: Ageing, cell death; Apoptosis; Biological and medical sciences; Cancer; Care and treatment; Causes of; Cell Biology; Cell death; Cell Line; Cell Nucleus - metabolism; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cleavage And Polyadenylation Specificity Factor - antagonists & inhibitors; Cleavage And Polyadenylation Specificity Factor - genetics; Cleavage And Polyadenylation Specificity Factor - metabolism; Cytoplasm - metabolism; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Library; Genetic aspects; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Human Genetics; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Molecular and cellular biology; Oncology; original-article; Physiological aspects; Polyadenylation; Prostate - metabolism; Prostate cancer; Protein Transport; Ribozymes; RNA; RNA, Small Interfering - genetics; Scavenger Receptors, Class A - genetics; Scavenger Receptors, Class A - metabolism; Tumor suppressor genes; Two-Hybrid System Techniques; United States; CSR1; RNA polyadenylation; cell death; CPSF3; RNA; Cell death; Polyadenylation; Inactivation; Carcinogenesis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2008.359

CSR1 (cellular stress response 1), a newly characterized tumor-suppressor gene, undergoes hypermethylation in over 30% of prostate cancers. Re-expression of CSR1 inhibits cell growth and induces cell death, but the mechanism by which CSR1 suppresses tumor growth is not clear. In this study, we screened a prostate cDNA library using a yeast two-hybrid system and found that the cleavage and polyadenylation-specific factor 3 (CPSF3), an essential component for converting heteronuclear RNA to mRNA, binds with high affinity to the CSR1 C terminus. Further analyses determined that the binding motifs for CPSF3 are located between amino acids 440 and 543. The interaction between CSR1 and CPSF3 induced CPSF3 translocation from the nucleus to the cytoplasm, resulting in inhibition of polyadenylation both in vitro and in vivo . Downregulation of CPSF3 using small interfering RNA induced cell death in a manner similar to CSR1 expression. A CSR1 mutant unable to bind to CPSF3 did not alter CPSF3 subcellular distribution, did not inhibit its polyadenylation activity and did not induce cell death. In summary, CSR1 appears to induce cell death through a novel mechanism by hijacking a critical RNA processing enzyme.