The p53 protein's association with tumours is probed further, leading to revelations about tumour growth
DESPITE their oxygen deficiency, which
should cause them to die or should
stunt their growth, turnours often continue to thrive. Why is this so? Recent
work by T G Graeber and colleagues of
the Stanford University School of
Medicine in the us suggests that the
absence of an all-purpose protein called p53 may be responsible for
the inexorable growth of WN
tumours (Nature, Vol 379, 1996).
The p53 has been associated
with tumour suppression.
However, the route of tumour
suppression that is followed by it
has turned out to be more subtle
than was previously believed. It
was commonly assumed that
normal cells had high levels of
p53, which, because of the protein's ability to bind to specific
cell-dividing DNA sequences,
could regulate the rate of cell
division. However, when the
protein mutated, this regulation
was removed and cells kept
dividing, thus causing a tumour
to form.
Later studies showed that
this hypothesis needed to be
modified because, contrary to
expectation, normal cells did not
express high levels of p53. It was only
when a situation of urgency arose, as
might be caused by DNA damage, or, as
Graeber and his team now show, by
oxygen starvation (hypoxia), that the
p53 gene was activated.
The research team is experiments
involved rat cells called fibroblasts that
had been engineered to express a
tumour promoting gene, c-myc. The
researchers compared the behaviour of
tumours that were induced by activating c-myc in cells lacking p53 with the
progression of those same tumours
when induced in fibroblasts containing
normal p53 genes, both under normal
and hypoxic conditions. The experiment found that hypoxia-induced death
was strongly correlated with the presence of p53. There was a 3.5 to four-fold
decrease in the frequency of cell death
caused by oxygen deprivation when p53
was lacking. In other words, p53-deficient cells survive better than normal
cells when they encounter low levels of
oxygen.
Further experimentation revealed
that after beginning with a 1: 1,000 ratio
of normal (p53pius) to deficient
(p53minus) cells, it took only seven
rounds of hypoxia for two-three days,
followed by recovery for three-five days,
@or most of the cells in the culture to be
of p53-deficient type. The findings suggest a route for tumour evolution. A
tumour is initiated, conceivably on
account of the malfunctioning of some
gene other than p53. Perhaps, as the
experiments reveal, the tumour survives
due to mutated p53 cells.
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