Cell Cycle Research Group
Among tumour-suppressor genes, the sequence at the INK4a/ARF locus
on chromosome 9 does double duty: it encodes two distinctly
different proteins. p14ARF and p16INK4a share
two exons, but differ in their first exon, resulting in very
different sequences, structures and functions. They operate
via different cellular pathways to arrest or execute mutation-damaged
cells before they can turn cancerous.
The Cancer Cell Cycle Research Group is investigating
how these proteins work, and which cellular targets each interacts
with. They have critical roles in maintaining the genetic integrity
of a wide range of cell types throughout the body. Consequently,
mutations that disrupt p14ARF or p16INK4a feature
in many different cancers; alterations affecting p14ARF and p16INK4a are
found in the majority of melanoma tumours.
A single-base change in the shared exons can
disrupt the activity of both genes. While around a third of
families with a history of melanoma have p16INK4a mutations,
our group has found that a small subset of melanoma-affected
families carry p14ARF specific mutations. The p14ARF tumour-suppressor
protein binds to a range of cellular targets, and we are investigating
what impact these novel partners have on the functions of p14ARF.
Our group recently proposed that the main
role of p14ARF is to attach another
protein, SUMO, to a variety of proteins, a process called sumoylation.
Sumoylation can alter the cellular location of some proteins,
and modulate the activity of others. We are exploring the downstream
consequences of p14ARF-induced sumoylation and the effect of
p14ARF mutations on protein sumoylation.
Some studies have reported that p14ARF,
acting alone can induce apoptosis – programmed cell death.
Others have suggested it is simply required to activate the
master apoptosis gene p53.
The Cell Cycle Research team has shown that p14ARF induces
apoptosis when it is co-expressed at normal physiological levels
in cells with functional p53;
it cannot induce apoptosis by itself.
Melanoma cancers are notoriously resistant
to chemotherapy. Through our research we have confirmed that
cells in which p14ARF is active
are sensitive to chemotherapy, but are resistant when p14ARF
is silenced. Genes regulated by p14ARF could
serve as alternative targets for new drugs to kill melanoma
tumours that have lost p14ARF protection.
