v-cbl, an oncogene from a dual-recombinant murine retrovirus that induces early B-lineage lymphomas.

Abstract

Cas NS-1 is an acutely transforming murine retrovirus that induces pre-B and pro-B cell lymphomas. Molecular cloning showed it was generated from the ecotropic Cas-Br-M virus by sequential recombinations with endogenous retroviral sequences and a cellular oncogene. The oncogene sequence shows no homology with known oncogenes but some similarity to the yeast transcriptional activator GCN4. A 100-kDa gag-cbl fusion protein, with no detectable kinase activity, is responsible for the cellular transformation. The cellular homologue of v-cbl, present in mouse and human DNA, is expressed in a range of hemopoietic lineages.The ability of retroviruses to recombine with host chromosomal DNA has enabled the identification of genes with cancer-causing potential, collectively known as oncogenes (for reviews, see refs. 1-3). From studies of avian and mammalian retroviruses numerous oncogenes have been isolated and this has led to dramatic progress in the definition and understanding of the molecular basis of cancer. We have been examining the tumors that develop in mice after infection with an ecotropic retrovirus called Cas-Br-M. This virus was originally isolated from a wild mouse of the Lake Casitas region of California (4) and induces T-and B-cell lymphomas, erythroleukemia, and myeloid leukemia with latent periods of 5-8 months (5). It remains unclear whether Cas-Br-M generates this range of tumors by infecting multipotential hemopoietic cells or by infecting cells committed to a lineage. Furthermore, the etiological agent in some of these tumors is a recombinant virus formed soon after inoculation (6). This class of murine retrovirus is termed mink cell focus-forming (MCF) virus and evolves by recombination between the infecting ecotropic virus and nonecotropic retroviral sequences present in the mouse genome (7,8).To determine the relative importance of Cas-Br-M and MCF viruses in the induction of hemopoietic neoplasms, cell-free extracts were prepared from a range of tumors arising in NFS/N mice inoculated at birth with Cas-Br-M (6). These extracts were inoculated into newborn NFS/N mice since it was reasoned if Cas-Br-M was the tumor-inducing virus, then each extract should produce a range of tumor phenotypes with a long latent period. Alternatively, if lineage-specific MCF viruses in the extracts were the dominant tumor-inducing agents, then the tumors should correspond to the primary tumor and the latency should be reduced. The results from 3 of 12 extracts tested were consistent with the latter possibility (6).One of the three extracts producing a high proportion of tumors with the same phenotype as the primary tumor and a reduced latency was called Cas NS-1. This extract was prepared from the spleen of a mouse with a pre-B cell lymphoma that developed 28 weeks after Cas-Br-M infection. Injection of the Cas NS-1 extract into newborn NFS/N mice resulted in a high proportion of pre-B cell lymphomas with a mean latent period of 16 weeks. This result indicated that a tumorigenic virus with a lineage preference...

Role of the adapter protein CRKL in signal transduction of normal hematopoietic and BCR/ABL-transformed cells

“…61 CBL is the cellular homolog of v-Cbl, the oncoprotein in the CAS NS-1 retrovirus which induces pre-B cell lymphomas and myelogenous leukemias in mice. [62][63][64] In mammalian cells, the specific function of CBL is not known, but the CBL homolog Sli-1 in C. elegans is a negative regulator of the epidermal growth factor receptor tyrosine kinase homologue Let-23. 65 Also, CBL-B, a CBL homolog with 50% sequence similarity has been recently cloned, 66 and it will be interesting if this can interact with CRKL in hematopoietic cells.…”

Tyrosine kinase activity of the EGF receptor is enhanced by the expression of oncogenic 70Z-Cbl

“…Cbl can be converted to an oncogenic protein either by a large carboxy truncation that generated v-Cbl, or by a small internal deletion at the amino terminus of the Ring ®nger that was identi®ed in a mutant allele of Cbl from the mouse pre-B cell lymphoma line, 70Z/3 ( Figure 1a) (Langdon et al, 1989;Blake et al, 1991;Andoniou et al, 1994). The v-Cbl truncation removes a large proline-rich SH3-binding region and the Ring ®nger domain to reveal a novel phosphotyrosine binding (PTB) domain that forms a direct association with the ZAP-70 tyrosine kinase and the EGF receptor (Lupher et al, 1996;Thien and Langdon, 1997).…”

CSF-1 stimulation induces the formation of a multiprotein complex including CSF-1 receptor, c-Cbl, PI 3-kinase, Crk-II and Grb2

“…Recently, CSF-1 has also been shown to induce the phosphorylation of the cytoplasmic c-Cbl which is the cellular homologue of the viral oncogene product v-cbl (Langdon et al, 1989;Tanaka et al, 1995;Wang et al, 1996). v-cbl has been shown to induce preB lymphomas and myelogenous leukemias, while the cellular homologue does not have this capacity, even when it is overexpressed.…”