A G-tract element in apoptotic agents-induced alternative splicing.
Alternative splicing of a single pre-mRNA transcript can produce protein isoforms that promote either cell growth or death. Here we show that Ro-31-8220 (Ro), an apoptotic agent that inhibits protein kinase C and activates the c-Jun N terminal kinase, decreased the proportion of the cell growth-promoting Bcl-xL splice variant. Targeted mutagenesis analyses narrowed down a critical sequence to a 16-nt G-tract element (Gt16). Transferring this element to a heterologous gene conferred Ro response on an otherwise constitutive exon. The Ro effect was reduced by okadaic acid, an inhibitor of protein phosphatases PP1 and PP2A, in a concentration-dependent manner. Search in the human genome followed by RT-PCR identified a group of genes that contain similar exonic G-tract elements and are responsive to Ro. Moreover, the Gt16 element also mediates the regulation of alternative splicing by other cell apoptosis-inducers particularly retinoic acid. Therefore, the G-tract element likely plays a role in the apoptotic agents-induced alternative splicing of a group of genes. The functions of these genes imply that this regulation will have impact on cell growth/death.
Hai
Yan
Y
Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College. Kunming, China.
Cao
Wenguang
W
Liu
Guodong
G
Hong
Say-Pham
SP
Elela
Sherif Abou
SA
Klinck
Roscoe
R
Chu
Jiayou
J
Xie
Jiuyong
J
D017398:Alternative Splicing / Q000187:drug effects; D017209:Apoptosis; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006147:Guanine / Q000032:analysis; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D019319:Okadaic Acid / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D012322:RNA Precursors / Q000737:chemistry*; D012333:RNA, Messenger / Q000737:chemistry*; D038621:Regulatory Sequences, Ribonucleic Acid; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism
D004791:Enzyme Inhibitors; D007211:Indoles; D012322:RNA Precursors; D012333:RNA, Messenger; D038621:Regulatory Sequences, Ribonucleic Acid; D051020:bcl-X Protein; D019319:Okadaic Acid; D006147:Guanine; D010744:Phosphoric Monoester Hydrolases; C064758:Ro 31-8220