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Andrew
Phillips, Ph.D.
E-mail:
Research Emphasis:
Although
cancer is a disease characterized by aberrant cell division, acquisition
of
mutations that drive inappropriate proliferation are not sufficient for
malignant progression.
The ability of cells to survive in a potentially hostile environment in
the absence of normal growth and survival signals is a prerequisite for full
malignancy.
Consequently, apoptosis (programmed cell death) places a constraint on
tumor development.
In addition, cell proliferation and apoptosis are coupled processes; many
oncogenes capable of driving proliferation also induce apoptosis.
It has been proposed that the antagonistic effect of oncogenes protects
the organism from tumorigenesis, since activation of a single oncogene in the
absence of compensating mutations can lead to elimination of the cell by
apoptosis. We are interested in understanding how oncogenes induce apoptosis,
the role of apoptosis in tumor suppression, and how this is overcome in cancer
cells.
Particular emphasis has been placed on investigating the E2F-Rb and p53
tumor suppressor pathways, since these pathways are disrupted in the majority
of, if not all, human cancers.
During development of a tumor, compensating mutations, for example loss
of p53 or p14ARF, can arise, inhibiting oncogene-stimulated
apoptosis.
Nevertheless, although tumor cells have, to a certain extent, escaped
this apoptotic mechanism, some retain enhanced sensitivity to apoptosis, a fact
that may underlie the efficacy of many chemotherapeutic protocols.
An understanding of the mechanism of oncogene-induced apoptosis will
provide insight into the development of tumors, allowing the development of
rational, anti-tumor therapies; either by exploiting the apoptotic pathways
stimulated by oncogenic activation, or by reactivating apoptotic pathways that
are disrupted during the development of the tumor.
Selected Publications:
A.C.Phillips, S.A.Bates, K.M.Ryan, K.Helin and K.H.Vousden. ‘Induction of
DNA synthesis and apoptosis are separable properties of E2F-1’
Genes
and development (1997)
11:1853-1863
S.A.Bates,
A.C.Phillips, F.Stott, P.A.Clark, G.Peters, R.L.Ludwig and K.H.Vousden
‘p14ARF
links the tumour suppressors RB and p53’.
Nature (1998) 395: 124-125.
Phillips, A.C., Ernst,
M., Bates, S., Rice, and Vousden, K.H. (1999) E2F-1 potentiates cell death by
blocking anti-apoptotic signaling pathways. Molecular Cell 4:771-781.
Irwin, M., Marin, M.C., Phillips, A.C., Seelan, R.S., Smith, D.I, Lui, W., Flores, E.R., Tsai, K.Y. Jacks, T., Vousden, K.H. and Kaelin,. W.G. Jr. (2000) Role for the p53 homolog p73 in E2F1-induced apoptosis. Nature 407:645-649.
Phillips, A.C. and Vousden, K.H. (2001). E2F-1 induced apoptosis. Apoptosis 6:173-182.