Tumour induction by activated abl involves tyrosine phosphorylation of the product of the cbl oncogene.
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.
Andoniou
C E
CE
Department of Biochemistry, University of Western Australia, Nedlands.
Thien
C B
CB
Langdon
W Y
WY
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D050722:Oncogene Protein v-cbl; D016374:Oncogene Proteins v-abl / Q000502:physiology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D050722:Oncogene Protein v-cbl; D016374:Oncogene Proteins v-abl; D011518:Proto-Oncogene Proteins; D015682:Retroviridae Proteins, Oncogenic; D014443:Tyrosine; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D016044:Fusion Proteins, bcr-abl; C067419:CBL protein, human; C493849:Cbl protein, mouse