MAD2B

The mitotic arrest deficient protein MAD2B is a well-defined anaphase-promoting complex/cyclosome (APC/C) inhibitor and a small subunit of DNA polymerase zeta. It is critical for mitotic control and DNA repair. However, the pathological role of MAD2B in kidney diseases has not been fully elucidated. In the present study, we aim to explore the role of MAD2B in the pathogenesis of renal tubulointerstitial fibrosis (TIF) and the underlying mechanism. By immunofluorescence and immunohistochemistry, we found an obvious MAD2B enhancement in tubular area of TIF patients and unilateral ureteral obstruction (UUO) mice...

MAD2B, an anaphase-promoting complex/cyclosome (APC/C) inhibitor and a small subunit of DNA polymerase ζ, is indispensible for mitotic checkpoint control and DNA repair. Previously, we established that MAD2B is expressed in glomerular and tubulointerstitial compartments and participates in high glucose-induced podocyte injury. However, its role in other renal diseases remains elusive. In the present study, we aim to illustrate the potential role of MAD2B in the pathogenesis of renal fibrosis. By immunofluorescence and Western blotting, we found MAD2B expression is obviously increased in tubulointerstitial fibrosis (TIF) patients and unilateral ureteral obstruction (UUO) mice...

The spindle assembly checkpoint (SAC) acts as a guardian against cellular threats that may lead to chromosomal missegregation and aneuploidy. Mad2, an anaphase-promoting complex/cyclosome-Cdc20 (APC/C(Cdc20)) inhibitor, has an additional homolog in mammals known as Mad2B, Mad2L2 or Rev7. Apart from its role in Polζ-mediated translesion DNA synthesis and double-strand break repair, Rev7 is also believed to inhibit APC/C by negatively regulating Cdh1. Here we report yet another function of Rev7 in cultured human cells...

The induction and maintenance of pluripotency requires the expression of several core factors at appropriate levels (Oct4, Sox2, Klf4, Prdm14). A subset of these proteins (Oct4, Sox2, Prdm14) also plays crucial roles for the establishment of primordial germ cells (PGCs). Here we demonstrate that the Mad2l2 (MAD2B, Rev7) gene product is not only required by PGCs, but also by pluripotent embryonic stem cells (ESCs), depending on the growth conditions. Mad2l2(-/-) ESCs were unstable in LIF/serum medium, and differentiated into primitive endoderm...

Appropriate repair of DNA lesions and the inhibition of DNA repair activities at telomeres are crucial to prevent genomic instability. By fuelling the generation of genetic alterations and by compromising cell viability, genomic instability is a driving force in cancer and ageing. Here we identify MAD2L2 (also known as MAD2B or REV7) through functional genetic screening as a novel factor controlling DNA repair activities at mammalian telomeres. We show that MAD2L2 accumulates at uncapped telomeres and promotes non-homologous end-joining (NHEJ)-mediated fusion of deprotected chromosome ends and genomic instability...

It is well documented that mitotic arrest deficiency (MAD)2B can inhibit the anaphase-promoting complex/cyclosome (APC/C) via cadherin (Cdh)1 and, consequently, can destroy the effective mitotic spindle checkpoint control. Podocytes have been observed to rapidly detach and die when being forced to bypass cell cycle checkpoints. However, the role of MAD2B, a cell cycle regulator, in podocyte impairment of diabetic nephropathy (DN) is unclear. In the present study, we investigated the significance of MAD2B in the pathogenesis of DN in patients, an animal model, and in vitro podocyte cultures...

BACKGROUND/AIMS: To assess the role of mitotic arrest-deficient 2-like protein 2 (MAD2B) in high glucose-induced injury in mouse glomerular endothelial cells (GEnCs). METHODS: GEnCs were cultured in vitro, and MAD2B protein levels were measured by Western blot in cells stimulated with high glucose (30 mM) for various periods of time. MAD2B and scrambled shRNA were introduced into GEnCs by liposomal transfection. Cell proliferation, apoptosis, nitric oxide (NO) production, and monolayer permeability were then measured in cells grown in the following conditions: control, high glucose treatment, MAD2B shRNA transfection with high glucose treatment, and scrambled shRNA transfection with high glucose treatment...

Human REV7 (also known as MAD2L2 and MAD2B) is involved in DNA repair, cell cycle regulation, gene transcription, and carcinogenesis. In this study, we evaluated the expression of REV7 in epithelial ovarian cancer (EOC) and analyzed the association between its expression and chemosensitivity in ovarian clear cell carcinoma (CCC) cells. Expression of REV7 in human EOC tissues was assessed by immunohistochemical staining. Expression was detected in the majority of EOCs (92.0%) with especially high levels of expression frequently observed in CCCs (73...

Diabetic encephalopathy may lead to cognitive deficits in diabetic patients and diminish quality of life. It has been shown that protracted hyperglycaemia is directly associated with neuronal apoptosis, which is involved in diabetic encephalopathy. The anaphase-promoting complex (APC) is essential for the survival of post-mitotic neurons. In our previous study, we found that the mitotic arrest deficient protein MAD2B, one of APC inhibitors, was expressed in neurons in central nervous system. However, whether MAD2B is involved in hyperglycaemia-induced apoptosis and thus takes part in diabetic encephalopathy is still unknown...

The development of primordial germ cells (PGCs) involves several waves of epigenetic reprogramming. A major step is following specification and involves the transition from the stably suppressive histone modification H3K9me2 to the more flexible, still repressive H3K27me3, while PGCs are arrested in G2 phase of their cycle. The significance and underlying molecular mechanism of this transition were so far unknown. Here, we generated mutant mice for the Mad2l2 (Mad2B, Rev7) gene product, and found that they are infertile in both males and females...

REV7 (also known as MAD2L2 and MAD2B) is involved in DNA repair, cell cycle regulation, gene expression, and carcinogenesis. In vitro studies show that REV7 interacts with several proteins and regulates their function. It has been reported that human REV7 is highly expressed in the adult testis by Northern blot analysis. However, the significance of REV7 in mammalian development has not been elucidated. Here, we present analyses of REV7-deficient (Rev7(-/-)) mice to clarify the significance of Rev7 in mouse development...

Single-minded 2 (Sim2) gene, located at the Down syndrome (DS) critical region, is thought to be particularly important because of its critical role in the development of the central nervous system (CNS) and its overexpression resulting in impairment of learning and memory which is similar to that in DS. However, its exact role in DS still remains elusive. Using a yeast two-hybrid interaction trap, we identified the mitotic arrest-deficient protein MAD2B as a novel Sim2 binding protein. Through confocal laser scanning microscopy, we found that Sim2 and MAD2B colocalized in rat cortex neurons...

Mitotic arrest deficient protein MAD2B, an enzyme involved in translesion DNA synthesis, has been implicated in several cancers. However, its role in human glioma has not been defined. In the present study, we investigated the expression levels of MAD2B in human gliomas and normal brain tissues, and determined whether depletion of MAD2B enhanced the sensitivity of glioma cells to ionizing radiation. Using reverse transcription-polymerase chain reaction and immunohistochemical analysis, MAD2B was found to be overexpressed in glioma specimens compared with normal brain tissue...

BACKGROUND: Although the mitotic arrest deficient protein MAD2B (MAD2L2) is thought to inhibit the anaphase promoting complex (APC) by binding to CDC20 and/or CDH1 (FZR1), its exact role in cell cycle control still remains to be established. METHODOLOGY/PRINCIPAL FINDINGS: Using a yeast two-hybrid interaction trap we identified the human clathrin light chain A (CLTA) as a novel MAD2B binding protein. A direct interaction was established in mammalian cells via GST pull-down and endogenous co-immunoprecipitation during the G2/M phase of the cell cycle...

DNA polymerase zeta (Polzeta) is an error-prone DNA polymerase involved in translesion DNA synthesis. Polzeta consists of two subunits: the catalytic REV3, which belongs to B family DNA polymerase, and the noncatalytic REV7. REV7 also interacts with REV1 polymerase, which is an error-prone Y family DNA polymerase and is also involved in translesion DNA synthesis. Cells deficient in one of the three REV proteins and those deficient in all three proteins show similar phenotype, indicating the functional collaboration of the three REV proteins...

BACKGROUND: Previously, we identified the mitotic arrest deficient protein MAD2B (MAD2L2) as a bona fide interactor of the renal cell carcinoma (RCC)-associated protein PRCC. In addition, we found that fusion of PRCC with the transcription factor TFE3 in t(X;1)(p11;q21)-positive RCCs results in an impairment of this interaction and, concomitantly, an abrogation of cell cycle progression. Although MAD2B is thought to inhibit the anaphase promoting complex (APC) by binding to CDC20 and/or CDH1(FZR1), its exact role in cell cycle control still remains to be established...

T cell factor 4 (TCF4) interacts with beta-catenin in the WNT signaling pathway and transactivates downstream target genes involved in cancer progression. To identify proteins that regulate TCF4-mediated biological responses, we performed a yeast two-hybrid screen to search for a TCF4-binding protein(s) and found that MAD2B interacts with TCF4. We confirmed that MAD2B is a TCF4-binding protein by co-immunoprecipitation. Using the TOPFLASH reporter assay, we found that MAD2B blocks TCF4-mediated transactivation...

Most current knowledge about DNA polymerase zeta (pol zeta) comes from studies of the enzyme in the budding yeast Saccharomyces cerevisiae, where pol zeta consists of a complex of the catalytic subunit Rev3 with Rev7, which associates with Rev1. Most spontaneous and induced mutagenesis in yeast is dependent on these gene products, and yeast pol zeta can mediate translesion DNA synthesis past some adducts in DNA templates. Study of the homologous gene products in higher eukaryotes is in a relatively early stage, but additional functions for the eukaryotic proteins are already apparent...

The mitogen-activated protein (MAP) kinases represent one of the most important classes of signaling cascades that are used by eukaryotic cells to sense extracellular signals. One of the major responses to these cascades is a change in cellular gene expression profiles mediated through the direct targeting of transcriptional regulators, such as the transcription factor Elk-1. Here we have identified human Rev7 (hRev7)/MAD2B/MAD2L2 as an interaction partner for Elk-1 and demonstrate that hRev7 acts to promote Elk-1 phosphorylation by the c-Jun N-terminal protein kinase (JNK) MAP kinases...

Aneuploidy and genetic instability are a hallmark of colorectal cancer and other solid tumors, and they are thought to enhance tumor progression. The gene MAD2L2 (mitotic arrest deficient 2-like 2) encodes the spindle checkpoint protein MAD2L2 (or MAD2B), a key component of a surveillance system that delays anaphase until all chromosomes are correctly oriented. Defects in this mitotic checkpoint are known to contribute to genetic instability, i.e., numerical and structural aberrations of chromosomes. We have previously identified MAD2L2 as significantly upregulated in locally restricted colorectal tumors by gene expression profiling...