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(+/-) mice were successfully generated, but repeated paired mating of Mad1(+/-) with Mad1(+/-) mice failed to produce a single Mad1(-/-) animal, suggesting that the latter genotype is embryonic lethal. In aging studies conducted for >18 months, Mad1(+/-) mice compared with control wild-type (wt) littermates showed a 2-fold higher incidence of constitutive tumors. Moreover, 42% of Mad1(+/-) (P < 0.03), but 0% of wt, mice developed neoplasia after treatment with vincristine, a microtubule depolymerization agent. Mad1(+/-) mouse embryonic fibroblasts (MEF) were found to be more prone than wt cells to become aneuploid; Mad1(+/-), 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.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1158/0008-5472.CAN-06-3326 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
MAD1 upregulation sensitizes to inflammation-mediated tumor formation.
PLoS Genet
October 2024
Department of Oncology/McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
Mitotic Arrest Deficient 1 (gene name MAD1L1), an essential component of the mitotic spindle assembly checkpoint, is frequently overexpressed in colon cancer, which correlates with poor disease-free survival. MAD1 upregulation induces two phenotypes associated with tumor promotion in tissue culture cells-low rates of chromosomal instability (CIN) and destabilization of the tumor suppressor p53. Using CRISPR/Cas9 gene editing, we generated a novel mouse model by inserting a doxycycline (dox)-inducible promoter and HA tag into the endogenous mouse Mad1l1 gene, enabling inducible expression of HA-MAD1 following exposure to dox in the presence of the reverse tet transactivator (rtTA).
View Article and Find Full Text PDFManipulation of the Myc Interactome to Enhance Nerve Regeneration in a Murine Model.
Ann Neurol
August 2024
Division of Neurology, Department of Medicine, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
Objective: This study was undertaken to explore manipulation of the Myc protein interactome, members of an oncogene group, in enhancing the intrinsic growth of injured peripheral adult postmitotic neurons and the nerves they supply. New approaches to enhance adult neuron growth properties are a key strategy in improving nerve regeneration.
Methods: Expression and impact of Myc interactome members c-Myc, N-Myc, Mad1, and Max were evaluated within naive and "preconditioned" adult sensory neurons and Schwann cells (SCs), using siRNA and transfection of CRISPR/Cas9 or luciferase reporter in vitro.
Caveolin-3 negatively regulates endocytic recycling of cardiac K channels.
Am J Physiol Cell Physiol
October 2023
Cyrus Tang Medical Institute, Soochow University, Suzhou, China.
Sarcolemmal ATP-sensitive potassium (K) channels play a vital role in cardioprotection. Cardiac K channels are enriched in caveolae and physically interact with the caveolae structural protein caveolin-3 (Cav3). Disrupting caveolae impairs the regulation of K channels through several signaling pathways.
View Article and Find Full Text PDFMad2 is dispensable for accurate chromosome segregation but becomes essential when oocytes are subjected to environmental stress.
Development
July 2023
Guangzhou Key Laboratory of Metabolic Diseases and Reproductive Health, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, China.
Accurate chromosome segregation, monitored by the spindle assembly checkpoint (SAC), is crucial for the production of euploid cells. Previous in vitro studies by us and others showed that Mad2, a core member of the SAC, performs a checkpoint function in oocyte meiosis. Here, through an oocyte-specific knockout approach in mouse, we reconfirmed that Mad2-deficient oocytes exhibit an accelerated metaphase-to-anaphase transition caused by premature degradation of securin and cyclin B1 and subsequent activation of separase in meiosis I.
View Article and Find Full Text PDFSchizophrenia-associated Mitotic Arrest Deficient-1 (MAD1) regulates the polarity of migrating neurons in the developing neocortex.
Mol Psychiatry
February 2023
Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea.
Article Synopsis
- Large-scale genome-wide association studies (GWAS) have linked the gene MAD1L1 to schizophrenia, but the exact mechanisms are not well understood.
- This study investigated the role of MAD1, a product of MAD1L1, in mouse and human brain development, revealing its crucial role in neuronal migration and neurite outgrowth during cortical development.
- The research found that MAD1 interacts with the kinesin-like protein KIFC3 to regulate vesicular trafficking and the Golgi apparatus, highlighting its importance in neuronal differentiation and suggesting that changes in MAD1 could contribute to schizophrenia.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!