Too MAD or not MAD enough: The duplicitous role of the spindle assembly checkpoint protein MAD2 in cancer

Mark Bates, Fiona Furlong, Michael F Gallagher, Cathy D Spillane, Amanda McCann, Sharon O'Toole, John J O'Leary

Research output: Contribution to journalArticle

Abstract

MAD2 is an intriguing protein, which has been associated with poor survival in cancer. Depending on the organ-specific cancer, either high expression or low expression levels have been correlated with low survival rates in patients. MAD2 is also a marker of contradiction. The normal function of MAD2 is to accumulate at kinetochores and generate a wait signal preventing the cell from progressing to anaphase of the cell cycle until the spindle microtubules have correctly aligned with the kinetochores on each chromosome. This process ensures that sister chromatids segregate correctly into each new daughter cell upon cellular division. Thus, the correct function of MAD2 and this crucial cell cycle checkpoint, the spindle assembly checkpoint (SAC), is essential for faithful replicative cell division, the prevention of chromosomal abnormalities and the development of cancer. Surprisingly when MAD2 is supressed for example through siRNA, this results in the induction of cellular senescence or cell cycle arrest. This is an inherent contradiction as normally the dispersement of MAD2 would signal to a cell that they should proceed to anaphase as spindle microtubules have correctly aligned with each chromatid for cell division. In the inverse setting; a second contradiction, high MAD2 expression in cancer patients generally correlates with abnormal chromosome number. However, in normal cells high expression of MAD2 would limit this by generating a wait signal to prevent the cell from proceeding through the cell cycle. In this review article we aim to make sense of the MADness and review the current knowledge of MAD2 and its role in cancer.

Original languageEnglish
Pages (from-to)11-21
Number of pages11
JournalCancer Letters
Volume469
Early online date05 Oct 2019
DOIs
Publication statusEarly online date - 05 Oct 2019
Externally publishedYes

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M Phase Cell Cycle Checkpoints
Kinetochores
Anaphase
Chromatids
Neoplasms
Cell Cycle Checkpoints
Proteins
Microtubules
Cell Division
Cell Cycle
Chromosomes
Cell Aging
Chromosome Aberrations
Small Interfering RNA
Siblings
Survival Rate
mycophenolic adenine dinucleotide
Survival

Bibliographical note

Copyright © 2019 Elsevier B.V. All rights reserved.

Cite this

Bates, Mark ; Furlong, Fiona ; Gallagher, Michael F ; Spillane, Cathy D ; McCann, Amanda ; O'Toole, Sharon ; O'Leary, John J. / Too MAD or not MAD enough: The duplicitous role of the spindle assembly checkpoint protein MAD2 in cancer. In: Cancer Letters. 2019 ; Vol. 469. pp. 11-21.
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Too MAD or not MAD enough: The duplicitous role of the spindle assembly checkpoint protein MAD2 in cancer. / Bates, Mark; Furlong, Fiona; Gallagher, Michael F; Spillane, Cathy D; McCann, Amanda; O'Toole, Sharon; O'Leary, John J.

In: Cancer Letters, Vol. 469, 05.10.2019, p. 11-21.

Research output: Contribution to journalArticle

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AU - Bates, Mark

AU - Furlong, Fiona

AU - Gallagher, Michael F

AU - Spillane, Cathy D

AU - McCann, Amanda

AU - O'Toole, Sharon

AU - O'Leary, John J

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N2 - MAD2 is an intriguing protein, which has been associated with poor survival in cancer. Depending on the organ-specific cancer, either high expression or low expression levels have been correlated with low survival rates in patients. MAD2 is also a marker of contradiction. The normal function of MAD2 is to accumulate at kinetochores and generate a wait signal preventing the cell from progressing to anaphase of the cell cycle until the spindle microtubules have correctly aligned with the kinetochores on each chromosome. This process ensures that sister chromatids segregate correctly into each new daughter cell upon cellular division. Thus, the correct function of MAD2 and this crucial cell cycle checkpoint, the spindle assembly checkpoint (SAC), is essential for faithful replicative cell division, the prevention of chromosomal abnormalities and the development of cancer. Surprisingly when MAD2 is supressed for example through siRNA, this results in the induction of cellular senescence or cell cycle arrest. This is an inherent contradiction as normally the dispersement of MAD2 would signal to a cell that they should proceed to anaphase as spindle microtubules have correctly aligned with each chromatid for cell division. In the inverse setting; a second contradiction, high MAD2 expression in cancer patients generally correlates with abnormal chromosome number. However, in normal cells high expression of MAD2 would limit this by generating a wait signal to prevent the cell from proceeding through the cell cycle. In this review article we aim to make sense of the MADness and review the current knowledge of MAD2 and its role in cancer.

AB - MAD2 is an intriguing protein, which has been associated with poor survival in cancer. Depending on the organ-specific cancer, either high expression or low expression levels have been correlated with low survival rates in patients. MAD2 is also a marker of contradiction. The normal function of MAD2 is to accumulate at kinetochores and generate a wait signal preventing the cell from progressing to anaphase of the cell cycle until the spindle microtubules have correctly aligned with the kinetochores on each chromosome. This process ensures that sister chromatids segregate correctly into each new daughter cell upon cellular division. Thus, the correct function of MAD2 and this crucial cell cycle checkpoint, the spindle assembly checkpoint (SAC), is essential for faithful replicative cell division, the prevention of chromosomal abnormalities and the development of cancer. Surprisingly when MAD2 is supressed for example through siRNA, this results in the induction of cellular senescence or cell cycle arrest. This is an inherent contradiction as normally the dispersement of MAD2 would signal to a cell that they should proceed to anaphase as spindle microtubules have correctly aligned with each chromatid for cell division. In the inverse setting; a second contradiction, high MAD2 expression in cancer patients generally correlates with abnormal chromosome number. However, in normal cells high expression of MAD2 would limit this by generating a wait signal to prevent the cell from proceeding through the cell cycle. In this review article we aim to make sense of the MADness and review the current knowledge of MAD2 and its role in cancer.

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