Transcriptional control of mitosis: deregulation and cancer

Abstract

Research over the past few decades has well established the molecular functioning of mitosis. Deregulation of these functions has also been attributed to the generation of aneuploidy in different tumor types. Numerous studies have given insight into the regulation of mitosis by cell cycle specific proteins. Optimum abundance of these proteins is pivotal to timely execution of mitosis. Aberrant expressions of these mitotic proteins have been reported in different cancer types. Several post-transcriptional mechanisms and their interplay have subsequently been identified that control the level of mitotic proteins. However, to date, infrequent incidences of cancer-associated mutations have been reported for the genes expressing these proteins. Therefore, altered expression of these mitotic regulators in tumor samples can largely be attributed to transcriptional deregulation. This review discusses the biology of transcriptional control for mitosis and evaluates its role in the generation of aneuploidy and tumorigenesis.

Keywords: aneuploidy; cancer; mitosis; mutation; transcription.

Figure 1

Molecular control of mitosis: regulation of mitotic proteins. Different regulatory mechanisms are shown.

Figure 2

Analysis of mutation and transcriptional alteration in mitotic genes. (A) Expression analysis of mitotic genes was done using ONCOMINE (4.4 research edition) database and mutation analysis was done using COSMIC (v67) according to the given workflow. (B) The two analyses were correlated to obtain the percentage of mutations in overexpressed and downregulated genes.

Figure 3

Cell cycle specific transcriptional regulation of a mitotic gene. Different cell cycle phases, mitotic gene, transcription start site, transcription factor (TF), and repressor are shown. “X” mark indicates “transcription off” condition and up arrow indicates “transcription on” condition. Dotted appearance indicates gradual reduction of recruitment of TF or repressor.

Figure 4

Role of transcription factors in regulation of mitosis: The left panel shows the involvement of various proto-oncogenic trans-factors as well as tumor suppressor transcription factors in regulation of phase specific expression of mitotic proteins. The right panel depicts the deregulation of transcription by gain of function mutations of proto-oncogene trans-factors as well as loss of function mutations of tumor suppressor trans-factors and onset of oncogenesis.