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]

The Tax The deregulation of the enzymatic machinery that controls the G 1 -to S-phase transition is causatively linked with viral transformation and tumorigenesis. Many viral oncoproteins from herpesviruses (vCyc and kCyc), adenoviruses (E1A), and papovaviruses (simian virus 40 [SV40] large T antigen and human papillomavirus E7) affect G 1 -specific cyclin-dependent kinases (CDKs) and/or their cognate substrate, retinoblastoma (Rb) protein (pRb) (22,25,50). CDK4 and its close relative CDK6 bind to cyclin D isotypes and, together with CDK2 complexes, integrate mitogenic and growth-inhibitory signals.

Replicated mammalian chromosomes condense to segregate during anaphase, and they de-condense at the conclusion of mitosis. Currently, it is not understood what the factors and events are that specify de-condensation. Here, we demonstrate that chromosome de-condensation needs the function of an inner nuclear membrane (INM) protein hsSUN1 and a membrane-associated histone acetyltransferase (HAT), hALP. We propose that nascently reforming nuclear envelope employs hsSUN1 and hALP to acetylate histones for de-compacting DNA at the end of mitosis.The eukaryotic nucleus is separated from other organelles by an envelope containing two membrane layers continuous with the endoplasmic reticulum. Nuclear membrane proteins fall into three categories according to their localization. The first group is the trans-nuclear membrane proteins resident in the nuclear pore complex (NPC).2 The second group contains the inner membrane proteins (INM), which include the lamin B receptor (LBR), emerin, and lamin-associated polypeptides (LAPs). The third group includes proteins underlying the nuclear membrane such as nuclear lamina (1). Functionally, the INM provides a physical barrier; the NPC serves for the transport of material between the nucleus and the cytoplasm (2); and the nuclear lamina erects a meshwork, which maintains nuclear structure and assists indirectly in DNA replication and RNA processing (3, 4).Most INM proteins are associated with the nuclear lamina. In a proteomic study of INM proteins, in addition to 13 known proteins, 67 uncharacterized open reading frames (ORFs) were identified (5

Human T-cell leukemia virus type 1 (HTLV-1) encodes a 40-kDa Tax phosphoprotein. Tax is a transcriptional activator which modulates expression of the viral long terminal repeat and transcription of many cellular genes. Because Tax is a critical HTLV-1 factor which mediates viral transformation of T cells during the genesis of adult T-cell leukemia, it is important to understand the processes which can activate or inactivate Tax function. Here, we report that ubiquitination of Tax is a posttranscriptional mechanism which regulates Tax function. We show that ubiquitination does not target Tax for degradation by the proteasome. Rather, ubiquitin addition modifies Tax in a proteasome-independent manner from an active to a less-active transcriptional form.