A 60 kd MDM2 isoform is produced by caspase cleavage in non-apoptotic tumor cells

Oncogene. 1998 Nov 19;17(20):2629-36. doi: 10.1038/sj.onc.1202206.

Abstract

The MDM2 oncogene product is a regulator of the p53 tumor suppressor. MDM2 is cleaved by Caspase 3 (CPP32) during apoptosis after aspartic acid-361, generating a 60 kd fragment. Here we report that human tumor cell lines often express high levels of a 60 kd MDM2 isoform (p60) in the absence of apoptosis. We demonstrate that p60 is a product of caspase cleavage of full length MDM2 after residue 361. The protease that cleaves MDM2 in non-apoptotic cells appears to be distinct from the apoptosis-specific Caspase 3, since Caspase 3 substrate poly(ADP-ribose) polymerase (PARP) is not cleaved in cells producing p60. The p60 form of MDM2 is a significant fraction of the p53-bound MDM2 protein in certain tumor cells, suggesting that it functions in the regulation of p53. p60 is also detected in breast tumors overexpressing MDM2. These observations suggest that MDM2 is regulated by caspase processing in non-apoptotic cells, and may account for the MDM2 proteins of similar mobility seen in tumors and other cell lines.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Apoptosis
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Caspase 3
  • Caspase Inhibitors
  • Caspases / metabolism*
  • Cytosol / metabolism
  • Epitopes / immunology
  • Female
  • Humans
  • Molecular Sequence Data
  • Molecular Weight
  • Neoplasm Proteins / immunology
  • Neoplasm Proteins / metabolism*
  • Nuclear Proteins*
  • Oligonucleotides, Antisense / pharmacology
  • Protease Inhibitors / pharmacology
  • Protein Isoforms / biosynthesis*
  • Protein Isoforms / immunology
  • Protein Precursors / metabolism*
  • Protein Processing, Post-Translational*
  • Proto-Oncogene Proteins / biosynthesis*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology
  • Proto-Oncogene Proteins c-mdm2
  • Staurosporine / pharmacology
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Caspase Inhibitors
  • Epitopes
  • Neoplasm Proteins
  • Nuclear Proteins
  • Oligonucleotides, Antisense
  • Protease Inhibitors
  • Protein Isoforms
  • Protein Precursors
  • Proto-Oncogene Proteins
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Staurosporine