Tumour induction by activated abl involves tyrosine phosphorylation of the product of the cbl oncogene

EMBO J. 1994 Oct 3;13(19):4515-23.

Abstract

v-cbl is the transforming gene of a murine retrovirus which induces pre-B cell lymphomas and myelogenous leukaemias. It encodes 40 kDa of a gag fusion protein which is localized in the cytoplasm and nucleus of infected cells. The c-cbl oncogene encodes a 120 kDa cytoplasmic protein and its overexpression is not associated with tumorigenesis. The c-cbl sequence has shown that v-cbl was generated by a truncation that removed 60% of the C-terminus. In this study, we carried out experiments to identify the position within cbl where the transition occurs between non-tumorigenic and tumorigenic forms. These experiments focused attention on a region of 17 amino acids which is deleted from cbl in the 70Z/3 pre-B lymphoma due to a splice acceptor site mutation. This mutation activates cbl's tumorigenic potential and induces its tyrosine phosphorylation. We also show that the expression of the v-abl and bcr-abl oncogenes results in the induction of cbl tyrosine phosphorylation, and that abl and cbl associate in vivo. These findings demonstrate that tyrosine-phosphorylated cbl promotes tumorigenesis and that cbl is a downstream target of the bcr-abl and v-abl kinases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Line
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cytoplasm / metabolism
  • Fusion Proteins, bcr-abl / physiology*
  • HeLa Cells
  • Humans
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Oncogene Protein v-cbl
  • Oncogene Proteins v-abl / physiology*
  • Phosphorylation
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-cbl
  • Retroviridae Proteins, Oncogenic / metabolism*
  • Tyrosine / metabolism
  • Ubiquitin-Protein Ligases*

Substances

  • Oncogene Protein v-cbl
  • Oncogene Proteins v-abl
  • Proto-Oncogene Proteins
  • Retroviridae Proteins, Oncogenic
  • Tyrosine
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases
  • Fusion Proteins, bcr-abl
  • CBL protein, human
  • Cbl protein, mouse