p53 regulates apoptosis in human retinoblastoma
T. M. Nork, G. L. Poulsen, L. L. Millecchia, R. G. Jantz and R. W. Nickells
Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, USA.
OBJECTIVES: To determine whether apoptosis is a significant mode of cell
death in human retinoblastoma (RB) and if it is regulated by the expression
of p53. METHODS: Apoptosis was analyzed using the criterion of
internucleosomal DNA degradation as determined by agarose gel
electrophoresis of DNA isolated from tumor specimens. Individual cells
undergoing apoptosis were identified using terminal transferase-mediated
biotin-dUTP nick end labeling (TUNEL) of fragmented DNA. The expression of
p53 and WAF1 (a protein involved in p53-mediated cell cycle arrest) in
human RB was determined by immunocytochemical analysis. The function of p53
in human RB cell lines was tested by transfecting them with a complementary
DNA encoding a temperature-sensitive isoform of murine p53 under the
control of a strong viral promoter. RESULTS: DNA from RB tumor specimens
showed a strong nucleosomal ladder of DNA fragments typical of apoptosis.
The TUNEL staining indicated that poorly and moderately differentiated
cells in tumors were undergoing DNA fragmentation. Immunoreactivity for p53
was variable. Cells expressing low levels of p53 seemed viable and
expressed WAF1. Cells expressing high levels of p53 were found immediately
adjacent to cells undergoing apoptosis. Human RB cells in culture that were
expressing a murine temperature-sensitive isoform of p53 died at
temperatures that allow this protein to assume a wild-type conformation.
CONCLUSIONS: Apoptotic cell death is prevalent in RB. The close association
of p53-immunoreactive cells and cells undergoing apoptosis in human tumors,
and the ability of exogenous p53 to stimulate cell death in cultured human
RB cells, suggests that p53 plays a role in regulating cell death in RB.
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