Complete loss of the tumor suppressor MAD2 causes premature cyclin B degradation and mitotic failure in human somatic cells
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MAD2 inhibits the anaphase-promoting complex when chromosomes are unattached to the mitotic spindle. It acts as a tumor suppressor gene because MAD2+/–cells enter anaphase early and display chromosome instability, leading to the formation of lung tumors in mice. Complete MAD2 inactivation has not been identified in human tumors, although partial defects are prevalent. By employing RNA interference in human somatic cells, we found that severe reduction of MAD2 protein levels results in mitotic failure and extensive cell death arising from defective spindle formation, incomplete chromosome condensation, and premature mitotic exit leading to multinucleation. Cyclin B is degraded prematurely in the MAD2 short interfering RNA-treated cells but not in MAD2+/– cells, suggesting an explanation for the spindle failure and mitotic catastrophe in the MAD2 knockdown cells. Thus, anaphase-promoting complex substrates exhibit distinct sensitivities in the presence of different MAD2 doses, which in turn determine MAD2's role as either a tumor suppressor or an essential gene.
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Complete downregulation of Mad2 in cells with intact Rb produces aneuploidy after a premature anaphase.
“Complete downregulation of Mad2 in cells with intact Rb produces aneuploidy after a premature anaphase 27 .”
From Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control (2004) · cites this paper as [27]
Cites
RNA interference is mediated by 21- and 22-nucleotide RNAsPreprint
Elbashir, S. M., Lendeckel, W., & Tuschl, T. (2001) · Genes & Development · doi:10.1101/gad.862301 · Cited by 3,310 · see citing works
Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cellsPreprint
Paddison, P. J., Caudy, A. A., Bernstein, E., Hannon, G. J., & Conklin, D. S. (2002) · Genes & Development · doi:10.1101/gad.981002 · Cited by 1,554 · see citing works
Feedback control of mitosis in budding yeast
Li, R., & Murray, A. W. (1991) · Cell · doi:10.1016/0092-8674(81)90015-5 · Cited by 1,174 · see citing works
Blangy, A., Lane, H. A., d'Hérin, P., Harper, M., Kress, M., & Niggt, E. A. (1995) · Cell · doi:10.1016/0092-8674(95)90142-6 · Cited by 952 · see citing works
The Anaphase-Promoting Complex
Peters, J. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00540-3 · Cited by 909 · see citing works
The KEN box: an APC recognition signal distinct from the D box targeted by Cdh1Preprint
Pfleger, C. M., & Kirschner, M. W. (2000) · Genes & Development · doi:10.1101/gad.14.6.655 · Cited by 733 · see citing works
MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells
Michel, L. S., Liberal, V., Chatterjee, A., Kirchwegger, R., Pasche, B., Gerald, W. L., Dobles, M., Sorger, P. K., Murty, V. V. V. S., & Benezra, R. (2001) · Nature · doi:10.1038/35053094 · Cited by 725 · see citing works
Self-citationThe Phosphatase Cdc14 Triggers Mitotic Exit by Reversal of Cdk-Dependent Phosphorylation
Visintin, R., Craig, K. L., Hwang, E. S., Prinz, S., Tyers, M., & Amon, A. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80286-5 · Cited by 725 · see citing works
Rieder, C. L., Cole, R. W., Khodjakov, A. L., & Sluder, G. (1995) · The Journal of Cell Biology · doi:10.1083/jcb.130.4.941 · Cited by 715 · see citing works
Identification of a Human Mitotic Checkpoint Gene: hsMAD2
Li, Y., & Benezra, R. (1996) · Science · doi:10.1126/science.274.5285.246 · Cited by 597 · see citing works
Self-citationFang, G., Yu, H., & Kirschner, M. W. (1998) · Genes & Development · doi:10.1101/gad.12.12.1871 · Cited by 597 · see citing works
Chromosome Missegregation and Apoptosis in Mice Lacking the Mitotic Checkpoint Protein Mad2
Dobles, M., Liberal, V., Scott, M. L., Benezra, R., & Sorger, P. K. (2000) · Cell · doi:10.1016/s0092-8674(00)80875-2 · Cited by 525 · see citing works
Self-citationControl of Cyclin Ubiquitination by CDK-Regulated Binding of Hct1 to the Anaphase Promoting Complex
Zachariae, W., Schwab, M., Nasmyth, K., & Seufert, W. (1998) · Science · doi:10.1126/science.282.5394.1721 · Cited by 511 · see citing works
Geley, S., Kramer, E., Gieffers, C., Gannon, J., Peters, J., & Hunt, T. (2001) · Journal of Cell Biology · doi:10.1083/jcb.153.1.137 · Cited by 462 · see citing works
The Mitotic Spindle: A Self-Made Machine
Karsenti, E., & Vernos, I. (2001) · Science · doi:10.1126/science.1063488 · Cited by 456 · see citing works
Stegmeier, F. P., Visintin, R., & Amon, A. (2002) · Cell · doi:10.1016/s0092-8674(02)00618-9 · Cited by 436 · see citing works
Role of Hec1 in Spindle Checkpoint Signaling and Kinetochore Recruitment of Mad1/Mad2
Lluesma, S. M., Stucke, V. M., & Nigg, E. A. (2002) · Science · doi:10.1126/science.1075596 · Cited by 427 · see citing works
Jaspersen, S. L., Charles, J. F., & Morgan, D. O. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80111-0 · Cited by 408 · see citing works
Tugendreich, S., Tomkiel, J. E., Earnshaw, W. C., & Hieter, P. (1995) · Cell · doi:10.1016/0092-8674(95)90336-4 · Cited by 364 · see citing works
Hemann, M. T., Fridman, J. S., Zilfou, J. T., Hernando, E., Paddison, P. J., Cordon‐Cardo, C., Hannon, G. J., & Lowe, S. W. (2003) · Nature Genetics · doi:10.1038/ng1091 · Cited by 354 · see citing works
Self-citationHaploinsufficiency of the Pten tumor suppressor gene promotes prostate cancer progression
Kwabi‐Addo, B., Giri, D., Schmidt, K., Podsypanina, K., Parsons, R. E., Greenberg, N. M., & Ittmann, M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.201167798 · Cited by 323 · see citing works
Peterson, J. B., & Ris, H. (1976) · Journal of Cell Science · doi:10.1242/jcs.22.2.219 · Cited by 281 · see citing works
APC-Mediated Proteolysis of Ase1 and the Morphogenesis of the Mitotic Spindle
Juang, Y., Huang, J. N., Peters, J., McLaughlin, M. E., Tai, C., & Pellman, D. S. (1997) · Science · doi:10.1126/science.275.5304.1311 · Cited by 242 · see citing works
APC-dependent proteolysis of the mitotic cyclin Clb2 is essential for mitotic exit
Wäsch, R., & Cross, F. R. (2002) · Nature · doi:10.1038/nature00856 · Cited by 231 · see citing works
Gorbsky, G. J., Chen, R., & Murray, A. W. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.141.5.1193 · Cited by 219 · see citing works
Mitotic checkpoints: from yeast to cancer
Wassmann, K., & Benezra, R. (2001) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(00)00161-1 · Cited by 195 · see citing works
Self-citationPds1 and Esp1 control both anaphase and mitotic exit in normal cells and after DNA damagePreprint
Tinker-Kulberg, R. L., & Morgan, D. O. (1999) · Genes & Development · doi:10.1101/gad.13.15.1936 · Cited by 164 · see citing works
Exit from Mitosis in Budding Yeast
Yeong, F. M., Lim, H. H., Padmashree, C. G., & Surana, U. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)80444-x · Cited by 158 · see citing works
Significance of MAD2 expression to mitotic checkpoint control in ovarian cancer cells.
Wang, X., Jin, D., Ng, R. W. M., Feng, H., Wong, Y. C., Cheung, A. L. M., & Tsao, S. W. (2002) · PubMed · Cited by 146 · see citing works
Draviam, V. M., Orrechia, S., Lowe, M., Pardi, R., & Pines, J. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.152.5.945 · Cited by 143 · see citing works
The spindle cycle in budding yeast
Winey, M., & O'Toole, E. T. (2001) · Nature Cell Biology · doi:10.1038/35050663 · Cited by 142 · see citing works
Mad2 transiently associates with an APC/p55Cdc complex during mitosis
Wassmann, K., & Benezra, R. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.19.11193 · Cited by 129 · see citing works
Self-citationWang, X. (2000) · Carcinogenesis · doi:10.1093/carcin/21.12.2293 · Cited by 105 · see citing works
Mad2 phosphorylation regulates its association with Mad1 and the APC/C
Wassmann, K., Liberal, V., & Benezra, R. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg071 · Cited by 101 · see citing works
Self-citationRole of p53 in UVB-Induced Apoptosis in Human HaCaT Keratinocytes
Henseleit, U., Zhang, J., Wanner, R., Haase, I., Kolde, G., & Rosenbach, T. (1997) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12340708 · Cited by 94 · see citing works
Gordon, D. M., & Roof, D. M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.231212498 · Cited by 58 · see citing works
Tracing the Pathway of Spindle Assembly Checkpoint Signaling
Gillett, E. S., & Sorger, P. K. (2001) · Developmental Cell · doi:10.1016/s1534-5807(01)00032-6 · Cited by 26 · see citing works
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Mad2 Overexpression Promotes Aneuploidy and Tumorigenesis in Mice
Sotillo, R., Hernando, E., Díaz-Rodríguez, E., Teruya-Feldstein, J., Cordón-Cardo, C., Lowe, S. W., & Benezra, R. (2007) · Cancer Cell · doi:10.1016/j.ccr.2006.10.019 · Cited by 612 · see citing works
Self-citationHernando, E., Nahlé, Z., Juan, G., Diaz-Rodriguez, E., Alaminos, M., Hemann, M., Michel, L., Mittal, V., Gerald, W., Benezra, R., et al. (2004) · Nature · doi:10.1038/nature02820 · Cited by 562 · see citing works
Self-citationTargeting Mitosis in Cancer: Emerging Strategies
Dominguez-Brauer, C., Thu, K. L., Mason, J. M., Blaser, H., Bray, M. R., & Mak, T. W. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.11.006 · Cited by 495 · see citing works
Schvartzman, J.-M., Duijf, P. H. G., Sotillo, R., Coker, C., & Benezra, R. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.04.017 · Cited by 181 · see citing works
Self-citationEarly aging–associated phenotypes in Bub3/Rae1 haploinsufficient mice
Baker, D. J., Jeganathan, K. B., Malureanu, L., Perez-Terzic, C., Terzic, A., & van Deursen, J. M. A. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200507081 · Cited by 175 · see citing works
- Authors
- Michel, L., Diaz-Rodriguez, E., Narayan, G., Hernando, E., Murty, V. V. V. S., & Benezra, R.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Cancer Biology and Genetics Program and Departments of Medicine and Pathology, Memorial Sloan–Kettering Cancer Center, New York, NY 10021; Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032; and Sloan–Kettering Division, Graduate School of Medical Sciences, Cornell University, New York, NY 10021
- Corresponding author
- Benezra, Robert
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-03-15
- Volume
- 101
- Issue
- 13
- Pages
- 4459-4464
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC384769
- OpenAlex
- W2084314276
- Cited by
- 188
- References
- 37
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 6 · 2020: 8 · 2019: 7 · 2018: 7 · 2017: 3 · 2016: 9 · 2015: 7 · 2014: 9 · 2013: 6 · 2012: 7
- FWCI
- 7.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Gredos (University of Salamanca) (publishedVersion, cc-by-nc-nd)
- Hispana (publishedVersion, cc-by-nc-nd)
- Funders
- Memorial Sloan-Kettering Cancer Center
- Brandeis University
- National Institutes of Health (5k08ca085731-06)
- National Cancer Institute (5K08CA085731-03, K08 CA085731)
- National Institute of General Medical Sciences (R01GM054601)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- Mad2, tumor suppressor, anaphase-promoting complex, cyclin B degradation, mitotic failure, mitotic catastrophe, spindle assembly, chromosomal instability, multinucleation, chromosome condensation, RNAi knockdown
- MeSH terms
- Base Sequence, Calcium-Binding Proteins, Cell Cycle, Chromosomes, Human, Humans, Microscopy, Fluorescence, Mitosis, Repressor Proteins, Transfection, Genes, Tumor Suppressor, Open Reading Frames, Cell Death, Gene Deletion, Cell Cycle Proteins, Cyclin B, Genes, Essential, Mad2 Proteins
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