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Cleavage of Retinoblastoma Protein during Apoptosis: An Interleukin 1ß-converting Enzyme-like Protease as Candidate¹

Department of Pharmacology, University of Pittsburgh School of Medicine, and Experimental Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213-2582

We had found that in an early stage of DNA damage-induced, p53-independent apoptosis, retinoblastoma (RB) protein is hypophosphorylated to a p115 form by an activated serine/threonine phosphatase. Here, we report that accompanying the internucleosomal fragmentation of DNA, the newly formed p115/hypo/RB was immediately cleaved into at least two fragments, p68 and p48. The RB cleavage activity possessed properties of interleukin 1ß-converting enzyme family. Addition of a specific tetrapeptide interleukin 1ß-converting enzyme inhibitor prevented cleavage of p115/hypo/RB and early apoptotic cells from undergoing further apoptosis. We suggest that activation of the RB phosphatase and protease may be involved in mediating the two physiological stages of apoptosis, commitment and execution, respectively.

¹ Supported by a James A. Shannon Director's Award (1 R55 AG/OD13300–01) from NIH and a start-up fund from the Department of Pharmacology, University of Pittsburgh School of Medicine (to Q. P. D.)

² To whom requests for reprints should be addressed, at Department of Pharmacology, University of Pittsburgh School of Medicine, and Experimental Therapeutics Program, University of Pittsburgh Cancer Institute, W952, Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213-2582.

Received 10/27/95. Accepted 12/ 8/95.

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