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T. Michael Nork, MD; Gretchen L. Poulsen; Lyndell L. Millecchia, PhD; Robert G. Jantz; Robert W. Nickells, PhD

Arch Ophthalmol. 1997;115(2):213-219.

Abstract
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 biotind-UTP 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.

Author Affiliations
From the Departments of Ophthalmology and Visual Sciences (Drs Nork and Nickells and Ms Poulsen and Mr Jantz) and Neurophysiology (Dr Nickells), University of Wisconsin, Madison; and the Department of Ophthalmology, West Virginia University School of Medicine, Morgantown (Dr Millecchia).

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