Aberrant splicing of cables gene, a CDK regulator, in human cancers.
Cables is a novel cell cycle regulatory protein that interacts with cdk2, cdk3, and cdk5. Cables inhibits cdk2 activity by enhancing cdk2 tyrosine 15 phosphorylation by Wee1, which consequently leads to inhibition of cell growth. Loss of Cables expression was found in many human cancers, especially colon and endometrial cancer. However, the role of the Cables gene in cancer development remains unclear. This study was undertaken to analyze transcripts of Cables gene in endometrial and colon cancers. The analysis of RT-PCR products of the Cables gene revealed shortened products in each sample along with the product of the expected size. Sequence analysis indicated that these shortened products represented eight intragenic deletions in Cables mRNA transcripts. Analysis of DNA from the same tumor sample failed to show genomic rearrangements corresponding to the transcripts containing deletions, suggesting that the deletions are the result of RNA splicing. Sequence analysis demonstrated that five of the deletions resulted from alternative splicing (splicing at the exon/intron boundary consensus sites), whereas the remaining three deletions resulted from aberrant splicing (splicing at sites not considered to be exon/intron boundary sites). All three aberrant splicing products were only detected in tumor tissues. Ectopic expression of one of the aberrant splicing products, which was detected in both endometrial and colon carcinomas, resulted in increased cell growth rate in human colon carcinoma HT-29 cells, suggesting a role as a dominant negative mutant.
Zhang
Hui
H
Departments of Pathology and Urology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Duan
Hai Ou
HO
Kirley
Sandra D
SD
Zukerberg
Lawrence R
LR
Wu
Chin-Lee
CL
D017398:Alternative Splicing; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D005260:Female; D019073:HT29 Cells; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D017384:Sequence Deletion
C486568:CABLES1 protein, human; D002352:Carrier Proteins; D016213:Cyclins; D010750:Phosphoproteins; D012333:RNA, Messenger; D018844:Cyclin-Dependent Kinases