Apoptosis of human melanoma cells induced by inhibition of B-RAF V600E involves preferential splicing of bimS

C. C. Jiang, F. Lai, K. H. Tay, A. Croft, H. Rizos, T. M. Becker, F. Yang, H. Liu, R. F. Thorne, P. Hersey*, X. D. Zhang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)

Abstract

Bim is known to be critical in killing of melanoma cells by inhibition of the RAF/MEK/ERK pathway. However, the potential role of the most potent apoptosis-inducing isoform of Bim, BimS, remains largely unappreciated. Here, we show that inhibition of the mutant B-RAFV600E triggers preferential splicing to produce BimS, which is particularly important in induction of apoptosis in B-RAFV600E melanoma cells. Although the specific B-RAFV600E inhibitor PLX4720 upregulates all three major isoforms of Bim, BimEL, BimL, and BimS, at the protein and mRNA levels in B-RAF V600E melanoma cells, the increase in the ratios of BimS mRNA to BimEL and BimL mRNA indicates that it favours BimS splicing. Consistently, enforced expression of B-RAFV600E in wild-type B-RAF melanoma cells and melanocytes inhibits BimS expression. The splicing factor SRp55 appears necessary for the increase in BimS splicing, as SRp55 is upregulated, and its inhibition by small interfering RNA blocks induction of BimS and apoptosis induced by PLX4720. The PLX4720-induced, SRp55-mediated increase in BimS splicing is also mirrored in freshly isolated B-RAFV600E melanoma cells. These results identify a key mechanism for induction of apoptosis by PLX4720, and are instructive for sensitizing melanoma cells to B-RAF V600E inhibitors.

Original languageEnglish
Article numbere69
Pages (from-to)1-14
Number of pages14
JournalCell Death and Disease
Volume1
DOIs
Publication statusPublished - Sep 2010
Externally publishedYes

Fingerprint

Dive into the research topics of 'Apoptosis of human melanoma cells induced by inhibition of B-RAF <sup>V600E</sup> involves preferential splicing of bimS'. Together they form a unique fingerprint.

Cite this