Mitotic arrest-deficient protein 1 (MAD1) is a component of the mitotic spindle assembly checkpoint. We have created a knockout mouse model to examine the physiologic consequence of reduced MAD1 function. Mad1 +/À mice were successfully generated, but repeated paired mating of Mad1 +/À with Mad1 +/À mice failed to produce a single Mad1 À/À animal, suggesting that the latter genotype is embryonic lethal. In aging studies conducted for >18 months, Mad1 +/À mice compared with control wild-type (wt) littermates showed a 2-fold higher incidence of constitutive tumors. Moreover, 42% of Mad1 +/À (P < 0.03), but 0% of wt, mice developed neoplasia after treatment with vincristine, a microtubule depolymerization agent. Mad1 +/À mouse embryonic fibroblasts (MEF) were found to be more prone than wt cells to become aneuploid; Mad1 +/À , but not wt, MEFs produced fibrosarcomas when explanted into nude mice. Our results indicate an essential MAD1 function in mouse development and correlate Mad1 haploinsufficiency with increased constitutive tumors. [Cancer Res 2007;67(1):160-6]

Human T-cell leukemia virus type I (HTLV-I) is the causative agent for adult T-cell leukemia (ATL

The Tax protein of human T-lymphotropic virus type 1 (HTLV-1), an oncoprotein that transactivates viral and cellular genes, plays a key role in HTLV-1 replication and pathogenesis. We used cDNA microarrays to examine Tax-mediated transcriptional changes in the human Jurkat T-cell lines JPX-9 and JPX-M which express Tax and Tax-mutant protein, respectively, under the control of an inducible promoter. Approximately 300 of the over 2000 genes examined were di erentially expressed in the presence of Tax. These genes were grouped according to their function and are discussed in the context of existing ®ndings in the literature. There was strong agreement between our results and genes previously reported as being Tax-responsive. Genes that were di erentially expressed in the presence of Tax included those related to apoptosis, the cell cycle and DNA repair, signaling factors, immune modulators, cytokines and growth factors, and adhesion molecules. Functionally, we provide evidence that one of these genes, the mixed-lineage kinase MLK-3, is involved in Tax-mediated NF-kB signaling. Our current results provide additional insights into Tax-mediated signaling. Oncogene (2001) 20, 4484 ± 4496.