Tpl-2 induces apoptosis by promoting the assembly of protein complexes that contain caspase-9, the adapter protein Tvl-1, and procaspase-3

J Cell Physiol. 2001 May;187(2):176-87. doi: 10.1002/jcp.1066.

Abstract

The Tpl-2 proto-oncoprotein promotes cellular proliferation when overexpressed in a variety of tumor cell lines. Here, we present evidence that when overexpressed in immortalized non-transformed cells, Tpl-2 induces apoptosis by promoting the activation of caspase-3 via a caspase-9-dependent mechanism, and that apoptosis is enhanced when Tpl-2 is co-expressed with the newly identified ankyrin repeat protein Tvl-1. The activation of caspase-3 by caspase-9 is known to depend on the assembly of a multimolecular complex that includes Apaf-1 and caspase-9. Data presented here show that co-expression of Tpl-2 with Tvl-1 promotes the assembly of a complex that involves several proteins that bind Apaf-1 including Tvl-1, itself, Tpl-2 and phosphorylated procaspase-9. More important, procaspase-3, which under normal growth conditions is not associated with the complex, binds Tvl-1 conditionally in response to Tpl-2-generated apoptotic signals. The conditional association of procaspase-3 with Tvl-1 promotes the in vivo proteolytic maturation of procaspase-3 by caspase-9, a process casually linked to apoptosis.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Sequence
  • Animals
  • Apoptosis / physiology*
  • Apoptotic Protease-Activating Factor 1
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Caspase 3
  • Caspase 9
  • Caspases / metabolism*
  • Cell Line
  • DNA-Binding Proteins
  • Enzyme Activation / physiology
  • Enzyme Precursors / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / enzymology
  • Gene Expression / physiology
  • Humans
  • Kidney / cytology
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding / physiology
  • Proteins / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Rats
  • Transcription Factors

Substances

  • APAF1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Apaf1 protein, mouse
  • Apaf1 protein, rat
  • Apoptotic Protease-Activating Factor 1
  • Carrier Proteins
  • DNA-Binding Proteins
  • Enzyme Precursors
  • Proteins
  • Proto-Oncogene Proteins
  • Rfxank protein, mouse
  • Transcription Factors
  • MAP Kinase Kinase Kinases
  • MAP3K8 protein, human
  • Map3k8 protein, mouse
  • Map3k8 protein, rat
  • CASP3 protein, human
  • CASP9 protein, human
  • Casp3 protein, mouse
  • Casp3 protein, rat
  • Casp9 protein, mouse
  • Casp9 protein, rat
  • Caspase 3
  • Caspase 9
  • Caspases