The RNA-binding protein Sam68 modulates the alternative splicing of Bcl-x.

Full Abstract

The RNA-binding protein Sam68 is involved in apoptosis, but its cellular mRNA targets and its mechanism of action remain unknown. We demonstrate that Sam68 binds the mRNA for Bcl-x and affects its alternative splicing. Depletion of Sam68 by RNA interference caused accumulation of antiapoptotic Bcl-x(L), whereas its up-regulation increased the levels of proapoptotic Bcl-x(s). Tyrosine phosphorylation of Sam68 by Fyn inverted this effect and favored the Bcl-x(L) splice site selection. A point mutation in the RNA-binding domain of Sam68 influenced its splicing activity and subnuclear localization. Moreover, coexpression of ASF/SF2 with Sam68, or fusion with an RS domain, counteracted Sam68 splicing activity toward Bcl-x. Finally, Sam68 interacted with heterogenous nuclear RNP (hnRNP) A1, and depletion of hnRNP A1 or mutations that impair this interaction attenuated Bcl-x(s) splicing. Our results indicate that Sam68 plays a role in the regulation of Bcl-x alternative splicing and that tyrosine phosphorylation of Sam68 by Src-like kinases can switch its role from proapoptotic to antiapoptotic in live cells.

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Author information

Author/s: Paronetto, Maria Paola (MP); Achsel, Tilman (T); Massiello, Autumn (A); Chalfant, Charles E (CE); Sette, Claudio (C);

Affiliation: Department of Public Health and Cell Biology, Section of Anatomy, University of Rome Tor Vergata, 00133 Rome, Italy.

Grants: R01HL72925 (Agency:NHLBI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: The Journal of cell biology (J Cell Biol), published in United States. (Language: eng)

Reference: 2007-Mar; vol 176 (issue 7) : pp 929-39

Dates: Created 2007/03/28; Completed 2007/05/29; Revised 2008/11/20;

PMID: 17371836, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Adaptor Proteins, Signal Transducing - genetics; metabolism
Alternative Splicing - genetics
Binding Sites - genetics
Cell Line
DNA-Binding Proteins - genetics; metabolism
Down-Regulation - physiology
Heterogeneous-Nuclear Ribonucleoprotein Group A-B - genetics; metabolism
Humans
Nuclear Proteins - genetics; metabolism

Nuclear Proteins - genetics; metabolism
Phosphorylation
Point Mutation - genetics
Protein Isoforms - genetics; metabolism
RNA, Messenger - genetics; metabolism
RNA, Small Interfering
RNA-Binding Proteins - genetics; metabolism
Up-Regulation - physiology
bcl-X Protein - genetics; metabolism

Associated Chemicals: Adaptor Proteins, Signal Transducing (0) ; BCL2L1 protein, human (0) ; DNA-Binding Proteins (0) ; FYB protein, human (0) ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B (0) ; KHDRBS1 protein, human (0) ; Nuclear Proteins (0) ; Protein Isoforms (0) ; RNA, Messenger (0) ; RNA, Small Interfering (0) ; RNA-Binding Proteins (0) ; SFRS1 protein, human (0) ; bcl-X Protein (0) ; hnRNP A1 (0)

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