Sign
out: Gastrointestinal pathology, hematopathology
and frozen sections.
In the United States, the overall lifetime
risk of colorectal cancer in the general population
is 6%, but it ranks as the second leading cause of
cancer-related deaths in men and women combined.
A stepwise model of colorectal tumorigenesis was
developed that includes mutations in the adenomatous
polyposis coli tumor-suppressor gene (APC) and oncogenic
KRAS mutations as early events. These are followed
by deletions on human chromosome 18q (LOH) and mutations
of TP53 with the transition to malignancy. This model
has been generally validated. However the genes targeted
by chromosome 18q deletions in colon cancers have
not been well defined and it appears that there may
be more than one important tumor suppressor gene on
18q that is altered in many cancers.
We have recently cloned a novel protein, Cables,
which maps to human chromosome 18q and inhibits growth
of cells in culture and tumor formation in nude mice.
Cables interacts with multiple cyclin dependent kinases
(cdks), including cdk2, and links the cdks and non-receptor
tyrosine kinases (Src, Abl, and Wee1). Cdk2 regulates
the G1/S phase transition and is essential for cell
cycle progression. Enhanced cdk2 tyrosine phosphorylation
occurs in the presence of Cables, which leads to decreased
kinase activity and diminished cell proliferation.
Cables also interacts with p53 and potentiates p53-induced
cell death.
Loss of Cables is found in up to 60%
of primary colon cancers, 90% of endometrial cancers,
and 50% of ovary, lung, bladder and head and neck
cancers. Thus, we believe that Cables may be a target
of the chromosome 18q deletions commonly seen in colon
and other cancers and may act as a tumor suppressor
gene. We have already created a Cables deficient mouse
which is viable. Our studies will define a novel target
for the deletions commonly seen on chromosome 18q.
Ultimately, these studies will lay the foundation
for new therapeutic approaches.
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