Regulation of PML-dependent transcriptional repression by pRB and low penetrance pRB mutants

Oncogene. 2002 Aug 15;21(36):5557-65. doi: 10.1038/sj.onc.1205666.

Abstract

The retinoblastoma protein (pRB) is thought to suppress tumorigenesis, in part, through interactions with E2F transcription factors. However, certain low penetrance pRB mutants substantially reduce tumor incidence despite having a minimal ability to bind E2F. These low penetrance mutants retain the ability to induce a senescence-like state, suggesting that they may suppress tumorigenesis through a senescence-associated process. Here, we identify a novel pRB function that is associated with senescence and which is retained by non-E2F binding low penetrance pRB mutants. It was found that pRB and these mutants substantially increased the production of PML nuclear bodies (NBs). In keeping with the role of PML in transcriptional repression, pRB also promoted PML-dependent transcriptional repression by the c-Myc antagonist Mad1. In a series of pRB-p130 chimeric proteins, the ability to increase NB production correlated with the ability to induce a senescence-like phenotype. However, neither NB formation nor PML function were required for pRB to induce the senescence-like response. Together, these observations indicate that a pRB-induced increase in PML NB formation is coordinated with, but separable from, the pRB-induced senescence program. The data further suggest that PML may contribute to an E2F-independent tumor suppressor function of pRB.

Publication types

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

MeSH terms

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • CDC2-CDC28 Kinases*
  • Cell Nucleus / metabolism*
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism
  • DNA-Binding Proteins / metabolism
  • Fluorescent Antibody Technique
  • Gene Expression Regulation
  • Genes, Dominant
  • Humans
  • Immunoblotting
  • Luciferases / metabolism
  • Mutagenesis, Site-Directed
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Plasmids
  • Promyelocytic Leukemia Protein
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Repressor Proteins*
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transcriptional Activation
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins
  • Zinc Fingers

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • MXD1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Promyelocytic Leukemia Protein
  • Repressor Proteins
  • Retinoblastoma Protein
  • Transcription Factors
  • Tumor Suppressor Proteins
  • PML protein, human
  • Luciferases
  • Protein Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases