|
|
Inactivation of the invasion inhibitory gene IIp45 by
alternative splicing in gliomas
Song SW, Fuller GN, Zheng H, Zhang W
Department of Pathology and Brain Tumor Center, University of Texas M.D.
Anderson Cancer Center, Houston, Texas 77030, USA.
The invasion inhibitory protein 45 (IIp45) we recently identified was
underexpressed in glioblastoma multiforme, the most malignant form of
glioma.
The IIp45 gene is located at chromosome 1p36 where frequent
deletions have been reported in various types of tumors, including gliomas,
raising the possibility that IIp45 may be a classic tumor suppressor gene
that can be inactivated by frequent point mutations.
To test this
hypothesis, we sequenced the IIp45 gene in 59 diffuse glioma samples of
different grades and histologic subtypes and identified a possible point
mutation or a rare polymorphism in only one sample (1.7%), suggesting that
IIp45 is not a classic tumor suppressor gene such as p53. Instead, reverse
transcription-PCR and subsequent sequencing results revealed a
tumor-specific IIp45 spliced isoform (IIp45S) in 20 of 59 (34%) gliomas
examined, particularly in glioblastoma multiformes, including native tissue
samples (15 of 25; 60%) and cell lines (5 of 5; 100%).
The alternative
splicing event is independent of 1p36 deletion, which is not common in
glioblastoma multiforme.
The IIp45S transcript was not detected in any of 18
normal organs, including fetal and adult brain.
We determined that the
IIp45S isoform results from exclusion of IIp45 exon 7 and encodes a variant
protein that carries a COOH terminus different from that of IIp45 due to a
frame-shift mutation.
IIp45S protein was undetectable in glioma tissues,
although IIp45S mRNA was prevalent.
We found that IIp45S, once translated,
is rapidly degraded by an ubiquitin-proteasome mechanism.
Thus, the IIp45
gene is inactivated by a tumor-specific alternative splicing that generates
an aberrant and unstable IIp45 isoform in infiltrative gliomas.
PMID: 15867349 [PubMed - in process]
|
