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From the Division of Neurosurgery,*
Arthur and Sonia
Labatt Brain Tumor Research Laboratory, Toronto; the Divisions of
Clinical Genetics
and
Pathology,
The Hospital for Sick Children,
Toronto; and the Department of Laboratory Medicine and
Pathobiology,§
The University of Toronto,
Toronto, Ontario, Canada
Astrocytic tumors frequently exhibit defects in the expression or
activity of proteins that control cell-cycle progression. Inhibition of
kinase activity associated with cyclin/cyclin-dependent kinase
co-complexes by cyclin-dependent kinase inhibitors is an important
mechanism by which the effects of growth signals are down-regulated. We
undertook the present study to determine the role of
p57KIP2 (p57) in human astrocytomas. We demonstrate
here that whereas p57 is expressed in fetal brain tissue,
specimens of astrocytomas of varying grade and permanent astrocytoma
cell lines do not express p57, and do not contain mutations of
the p57 gene by multiplex-heteroduplex analysis.
However, the inducible expression of p57 in three
well-characterized human astrocytoma cell lines (U343 MG-A, U87
MG, and U373 MG) using the tetracycline repressor system leads
to a potent proliferative block in G1 as determined by
growth curve and flow cytometric analyses. After the induction of
p57, retinoblastoma protein, p107, and E2F-1
levels diminish, and retinoblastoma protein is shifted to a
hypophosphorylated form. Morphologically, p57-induced
astrocytoma cells became large and flat with an expanded cytoplasm. The
inducible expression of p57 leads to the accumulation of
senescence-associated ß-galactosidase marker within all astrocytoma
cell lines such that 
75% of cells were positive at 1 week
after induction. Induction of p57 in U373 astrocytoma cells generated a
small population of cells (15%) that were nonviable,
contained discrete nuclear fragments on Hoechst 33258 staining,
and demonstrated ultrastructural features characteristic of apoptosis.
Examination of bax and poly-(ADP ribose) polymerase levels showed no
change in bax, but decreased expression of poly-(ADP ribose)
polymerase after p57 induction in all astrocytoma cell lines. These
data demonstrate that the proliferative block imposed by p57 on human
astrocytoma cells results in changes in the expression of a number of
cell cycle regulatory factors, cell morphology, and a
strong stimulus to cell senescence.
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