Inactivation of retinoblastoma (RB) tumor suppressor by oncogenic isoforms of the p53 family member p73

Thorsten Stiewe; Jens Stanelle; Carmen C Theseling; Barbara Pollmeier; Michaela Beitzinger; Brigitte M Pützer

doi:10.1074/jbc.M300357200

Inactivation of retinoblastoma (RB) tumor suppressor by oncogenic isoforms of the p53 family member p73

J Biol Chem. 2003 Apr 18;278(16):14230-6. doi: 10.1074/jbc.M300357200. Epub 2003 Feb 12.

Authors

Thorsten Stiewe¹, Jens Stanelle, Carmen C Theseling, Barbara Pollmeier, Michaela Beitzinger, Brigitte M Pützer

Affiliation

¹ Center for Cancer Research and Cancer Therapy, Institute of Molecular Biology, University of Essen, Medical School, Germany.

PMID: 12584188
DOI: 10.1074/jbc.M300357200

Abstract

The p53 family includes three members that share significant sequence homology, yet exhibit fundamentally different functions in tumorigenesis. Whereas p53 displays all characteristics of a classical tumor suppressor, its homologues p63 and p73 do not. We have previously shown, that NH(2)-terminally truncated isoforms of p73 (Delta TA-p73), which act as dominant-negative inhibitors of p53 are frequently overexpressed in cancer cells. Here we provide evidence that Delta TA-p73 isoforms also affect the retinoblastoma protein (RB) tumor suppressor pathway independent of p53. Delta TA-p73 isoforms inactivate RB by increased phosphorylation, resulting in enhanced E2F activity and proliferation of fibroblasts. By inactivating the two major tumor suppressor pathways in human cells they act functionally analogous to several viral oncoproteins. These findings provide an explanation for the fundamentally different functions of p53 and p73 in tumorigenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenoviridae / genetics
Blotting, Western
Cell Division
Culture Media, Serum-Free / pharmacology
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
Cyclin-Dependent Kinase Inhibitor p21
Cyclins / metabolism
DNA-Binding Proteins / chemistry
DNA-Binding Proteins / metabolism*
Electrophoresis, Polyacrylamide Gel
Fibroblasts / metabolism
Genes, Dominant
Genes, Tumor Suppressor
Humans
Luciferases / metabolism
Membrane Proteins*
Microscopy, Fluorescence
Neoplasms / metabolism
Nuclear Proteins / chemistry
Nuclear Proteins / metabolism*
Phenotype
Phosphoproteins / chemistry
Phosphoproteins / metabolism*
Phosphorylation
Plasmids / metabolism
Protein Isoforms
Protein Structure, Tertiary
Retinoblastoma Protein / metabolism*
Trans-Activators / chemistry
Trans-Activators / metabolism*
Transcription Factors
Transfection
Tumor Protein p73
Tumor Suppressor Protein p53 / antagonists & inhibitors
Tumor Suppressor Proteins

Substances

CDKN1A protein, human
CKAP4 protein, human
Culture Media, Serum-Free
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p21
Cyclins
DNA-Binding Proteins
Membrane Proteins
Nuclear Proteins
Phosphoproteins
Protein Isoforms
Retinoblastoma Protein
TP63 protein, human
TP73 protein, human
Trans-Activators
Transcription Factors
Tumor Protein p73
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
Luciferases