An overview of MAD2 protein, its functions and its association with Cancer

An overview of MAD2 protein, its functions and its association with Cancer
Yalda Zhoolideh,^1,*
1. Islamic Azad University Of Tabriz
Introduction: The spindle assembly checkpoint (SAC) involves the MAD proteins; MAD1, MAD2, BUBR1 (MAD3), and BUB1. The Mitotic-arrest deficiency 2 (MAD2) is a key component of SAC function and controls cell entry from the metaphase to the anaphase stage. MAD2 are located in spindle poles, kinetochores and cytoplasm of early prometaphase LLC-Pk cells and capable of heterodimerization and thereby recruits free MAD2 from the cytosol. The MAD2 gene was first discovered in the yeast Saccharomyces cerevisiae and also is present in most kinetochores in the first meiotic division and remains associated with the kinetochore throughout MI. It does not dissociate during metaphase and anaphase, as is the case for mitosis. The human orthologues of this protein are MAD2L1 and MAD2L2. MAD2L1 and MAD2L2 gene related to each other and located on chromosome 1.
Methods: Articles related to the subject were searched on two sites of Science Direct and Google scholar, and 25 articles that examined MAD2 protein and its association with Cancer were included in the study.
Results: The entry from metaphase to anaphase is accomplished by the separation of sister chromatids. The cell cycle regulatory mechanism that prevents these chromatids from being separated is called the spindle checkpoint, which has a protective role against chromosomal aberrations and MAD2 has a prominent role in this process. The size of MAD2 is 25 kDa and consists of two parts with different features called Open-MAD2 (O-MAD2) and Closed-MAD2 (C-MAD2). Kinetochores devoid of microtubules maintain a tight complex of MAD2 with another SAC protein named Mad1. Binding of MAD1 to MAD2 leads to a complex that acts as a template for MAD2 activity and binds to Cdc20. The MAD2 binding site to Cdc20 is held in a binding pocket of MAD2 by a mobile element called the “safety belt”. This interaction is essential for SAC function. Disruption of MAD2 expression can cause various cancers, including ovarian, colorectal, breast, bladder, lung and etc. In the recent years, researchers inquire the treatment of cancer based on the selective killing of mitotic checkpoint competent cells, and assay the effect of MAD2 expression on cellular sensitivity to checkpoint-targeting anticancer drugs. However, studies have shown that different ovarian cancer subtypes exhibit different expressions of MAD2. There is no strong evidence that low levels of MAD2 expression cause recurrence of cancer. As expected, elevated levels of MAD2 expression are directly associated with increased chances of surviving ovarian cancer patients but is different from other types of cancers. In ovarian and breast cancers, it has been found that the P53 and BRCA1 genes are responsible for regulating MAD2 expression. In addition, research has shown that silencing of the MAD2 gene by siRNAs can be one of the therapeutic approaches in ovarian cancer cases. In some sort of the lung cancer (NSCLC), MAD2 overexpression has been observed in most cases. It also appears that patients with tumors with MAD2 overexpression have a shorter life expectancy. Significant increases in MAD2 expression can also be observed in colorectal cancer and bladder cancer. On the other hand, in cases of gastric cancer, there was a significant increase in MAD2 expression compared to normal tissues.
Conclusion: MAD2 expression as a prognostic marker for human malignant cancers and according to research and observations, we can find that MAD2 increases in some types of cancers and decreases in others and is one of the important factors in regulating the cell cycle. In fact, it can be said that alterations in the expression of this protein can lead to cancer awareness. Consequently, prophylactic medications may be used instead of chemotherapy after cancer. However, according to available studies, further studies are needed to understand the exact mechanism of this disease.
Keywords: MAD2, Spindle assembly checkpoint, Cancer