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Correlated with the loss of functional tumor suppressors, transcriptional deregulation of Plk1 is reported in various cancers and associated with CIN and oncogenic transformation In co-ordination with the loss-of-function of tumor suppressors, the overexpression of this protein is associated with CIN and cancer 77 — Oncoproteins like EWS-Fli1 and Myc upregulate expression of aurora family proteins through binding on promoter response elements. On the other hand, tumor suppressors like p53, Brd4 also influence expression of Aurora kinases 83 — In fact, the altered expression of Aurora kinases are potential markers of cancer progression Regulated expression of kinetochore protein Hec1 is directly related to phosphorylation-mediated inactivation of Rb during the course of cell cycle.
Beside this, the CREB family of oncoprotein transcription factors has been shown to upregulate the levels of kinetochore protein Hec1 Disrupted pRb function is associated with transcriptional upregulation of Hec1, which may cause aneuploidy and tumor formation 89 , The initial events of mitosis are followed by chromosomal alignment at the equatorial plane of the cell during metaphase.
The amphitelic metaphase alignment precedes SAC release, chromosomal segregation, and entry into anaphase. Different transcription factors and chromatin modifiers regulate cell cycle specific promoter activities of these genes 68 , 92 , Upon genotoxic stress, Cdc20 expression is indirectly suppressed by p53 through pdependent mechanism On the other hand, a direct p53 binding element has been identified on the CDC20 promoter and shown to bring about repression of transcription through chromatin remodeling Similarly, direct recruitment of p53 on the promoter consensus element brings about chromatin remodeling and the repression of Mad1 expression Expression of Mad2 is regulated by E2F in a cell cycle-dependent manner.
Rb inactivation leads to aberrant Mad2 expression by deregulating E2F activity and contributes to mitotic defects and aneuploidy Cancer-associated defects in these tumor suppressors contribute to the abnormal expression of these proteins and a flawed SAC. Indeed, transcriptional abnormalities including differential promoter methylation of these SAC proteins are potential markers of cancers of various origins 97 , Their deregulated expressions are associated with CIN phenotype and incidence of cancer 6. The final stages of mitosis involve cytokinesis and mitotic exit.
Along with mitotic kinases like Aurora, Polo, and related families, some other molecular components also regulate this stage of the cell cycle. Protein regulator of cytokinesis 1 PRC1 and the guanine nucleotide exchange factor, Ect2, the two major molecules of cytokinesis have been related with cancer-associated altered expressions and CIN 6. In conclusion, we have summarized a number of reports from the ever-growing lists of proto-onco gene as well as tumor suppressor trans-factors in regulation of mitosis and their deregulation in tumor background Table 1. Table 1. Role of proto-oncoprotein and tumor suppressor transcription factors in mitosis and involvement in oncogenesis.
The role of transcriptional regulatory pathways behind the incidence of tumorigenesis remains an enigma. For a number of key cell cycle regulators, the transcriptional control represents an evolutionarily conserved mechanism to precisely maintain their abundance, working in conjunction with miRNA mediated silencing, translational control, and ubiquitin-mediated degradation 23 , 26 , , Among these cell cycle regulators, a defined set of factors stringently control mitotic entry, progression, and exit.
The interplay among these factors is naturally adjusted by their abundance. Abnormality in this abundance is associated with the occurrence of aneuploidy, a hallmark of cancer 2 , 8 , In this review, we have discussed the maintenance of protein levels of the mitotic players whose transcription is regulated in a cell cycle specific manner. We further discussed the deregulation of their transcriptional control, working in concert with cancer onset. In this regard, mutations in various tumor suppressors and proto-oncogenes acting as co-factors of transcription are found to disharmonize the relative protein levels, rather than mutations in the mitotic genes themselves.
Besides this, a few mitotic genes are reported to participate in transcriptional control. Furthermore, the list of transcripts whose transcription is affected by certain cell cycle or developmental transitions is being expanded owing to new genome-wide approaches. Answer to many open questions regarding the interplay between transcriptional regulation and mitotic progression will make an important contribution to the understanding of cell cycle control.
This, in turn, will help to dissect the involvement of cell cycle progression in the onset of tumorigenesis. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Jallepalli PV, Lengauer C. Chromosome segregation and cancer: cutting xthrough the mystery. Nat Rev Cancer 1 — Aneuploidy and cancer.
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