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CSR1 Inducing Cell Death Through Inactivation Of CPSF3
Author(s) -
Luo Jianhua,
Zhu Zehua,
Yu Yan
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1122.9
Subject(s) - polyadenylation , programmed cell death , microbiology and biotechnology , mutant , biology , rna splicing , cytoplasm , rna , chemistry , gene , biochemistry , apoptosis
CSR1, a newly characterized tumor suppressor gene located in the 8p21 region, undergoes hypermethylation of its promoter and exon 1 regions in over 30% of prostate cancers. Re‐expression of CSR1 inhibits cell growth and induces cell death, but the mechanisms of CSR1‐mediated tumor suppressor activity are not clear. In this study, a Yeast‐two hybrid screening identified proteins interacting with the C‐terminus of CSR1. The cleavage and poly‐adenylation specific factor 3 (CPSF3), an essential component for converting hnRNA to mRNA, bound with CSR1 C‐terminus with high affinity. Analysis of a series of GST‐CSR1 mutants found the binding motifs for CPSF3 located at sequence between amino acids 440–513. The interaction between CSR1 and CPSF3 induced CPSF3 translocation from nucleus to cytoplasm, resulting in nuclear inhibition of the polyadenylation activity both in vitro and in vivo. Down‐regulation of CPSF3 using siRNA induced cell death in a manner similar to those induced by CSR1 expression. CSR1 mutant unable to bind to CPSF3 did not alter CPSF3 subcellular distribution, and did not inhibit its polyadenylation activity nor induce cell death. In summary, CSR1 appears to induce cell death through a novel mechanism by hijacking a critical RNA processing enzyme.