Journal
ONCOGENE
Volume 24, Issue 26, Pages 4271-4280Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1208587
Keywords
intra-exonic pre-mRNA splicing; aberrant pre-mRNA splicing; KIT mutation; KIT; gastrointestinal stromal tumor
Funding
- NCI NIH HHS [N0-CM-17003, R25 CA57730, U01-CA70172-01, CA16672] Funding Source: Medline
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We report a new mechanism of aberrant pre-mRNA splicing resulting in constitutive activation of a mis-spliced oncoprotein (KIT) leading to malignancy(gastrointestinal stromal tumor) in contrast to loss of function of mis-spliced proteins resulting in diverse human diseases in the literature. The mechanisms of three consecutive molecular events, deletion of noncoding and coding regions encompassing the 30 authentic splice site, creation of a novel intra-exonic pre-mRNA 30 splice acceptor site leading to in-frame loss of 27 nucleotides ( nine amino acids; Lys550-Lys558), and the mechanism of constitutive activation of the mis-spliced KIT are elucidated. Loss of a peptide in a critical location unleashed the protein from autoinhibition ( as evidenced by three-dimensional structural analysis), causing KIT to become constitutively activated and resulting in the GIST phenotype. We also demonstrated that only one of the following two exonic splicing enhancers is sufficient for inclusion of the KIT exon 11 in vivo: AACCCATGT ( nucleotides 2 - 10 from the 50 end, which are recognized by SC35, SRp55, and SF2/ASF) or GGTTGTTGAGG ( nucleotides 27 - 37 from the 50 end, which are recognized by SC35 and SRp55), suggestive of exonic enhancer redundancy.
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