| Slow transforming murine retroviruses can induce leukemia in their host by insertional mutation of cellular proto-oncogenes or tumor suppressor genes. Following retroviral integration, cellular genes may become aberrantly expressed through activation by viral promoter or enhancer sequences. The abnormal expression of a certain proto-oncogene may then provide a growth advantage to the target cell and contribute to malignant transformation. During the past years an important number of critical cancer genes have been identified in these leukemias by proviral tagging.; We have characterized Gris1 as a novel common integration site in 13% of Graffi murine retrovirus-induced leukemias. This novel locus was located on mouse chromosome 6, 75 to 85 Kbp upstream the cyclin D2 gene. Integrations in Gris1 were shown to activate the expression of the 6.5 kb major transcript of the cyclin D2 gene and also a smaller 1.1 kb transcript that we have shown to represent an alternative transcript encoding a 17 Kda truncated cyclin D2 protein. The protein is detected at high level in the Gris1 tumors and also in normal tissue mainly in brain and ovaries (Denicourt et al., 2002). We also have reported the existence of several ESTs in the databases encoding a similar truncated cyclin D2 in humans.; We demonstrated that the overexpression of the truncated cyclin D2 can transform primary mouse embryo fibroblasts in conjunction with activated Ras. We also showed that the human homolog transcript of the truncated cyclin D2 is overexpressed in some type of primary human brain tumors. As opposed to the subcellular localization of the cyclin D2 protein, this truncated D2 was never observed in the nucleus of NIH 3T3 fibroblasts but was predominantly localized to a not yet characterized cytoplasmic structure. Despite the fact that this truncated cyclin represent half of the full length cyclin D2, we have shown that this isoform still retains the ability to interact with CDK4. |
