Abstract
The class I cyclin family is a well-studied group of structurally conserved proteins that interact with their associated cyclin-dependent kinases (Cdks) to regulate different stages of cell cycle progression depending on their oscillating expression levels. However, the role of class II cyclins, which primarily act as transcription factors and whose expression remains constant throughout the cell cycle, is less well understood. As a classic example of a transcriptional cyclin, cyclin C forms a regulatory sub-complex with its partner kinase Cdk8 and two accessory subunits Med12 and Med13 called the Cdk8-dependent kinase module (CKM). The CKM reversibly associates with the multi-subunit transcriptional coactivator complex, the Mediator, to modulate RNA polymerase II-dependent transcription. Apart from its transcriptional regulatory function, recent research has revealed a novel signaling role for cyclin C at the mitochondria. Upon oxidative stress, cyclin C leaves the nucleus and directly activates the guanosine 5’-triphosphatase (GTPase) Drp1, or Dnm1 in yeast, to induce mitochondrial fragmentation. Importantly, cyclin C-induced mitochondrial fission was found to increase sensitivity of both mammalian and yeast cells to apoptosis. Here, we review and discuss the biology of cyclin C, focusing mainly on its transcriptional and non-transcriptional roles in tumor promotion or suppression.
Highlights
Cyclins, so named as this eukaryotic protein family displayed cycling expression patterns throughout the cell cycle [1], formed the basis of research resulting in a broad understanding of cell cycle control [2]
We summarize the current knowledge on cyclin C biology including its dual role in eliciting stress signaling while highlighting potential implications relevant to cancer and cancer therapy
Cdk8-dependent kinase module (CKM) components suchgroove as Med12 components such asmay cyclin C contains a unique, highly conserved which is located between the two cyclin repeats that may serve to interact with other CKM members
Summary
Named as this eukaryotic protein family displayed cycling expression patterns throughout the cell cycle [1], formed the basis of research resulting in a broad understanding of cell cycle control [2]. Cyclins and their Cdk partners have many functions other than cell cycle control including proteolytic degradation, programmed cell death, DNA damage repair, metabolism, stem cell self-renewal, and spermatogenesis [5] This group can be divided into non-cycling transcription factors (class II) and other (class III) cyclins (Table 1). Despite the pro-oncogenic effects associated with Cdk overexpression, these observations allude to a tumor suppressive role of cyclin C This inconsistency may be explained by cell-type specific differences in cyclin C-Cdk transcriptional control. An alternative possibility to explain this conundrum may stem from the non-canonical role that cyclin C plays as a key mediator of stress signaling [33] In this scenario, the stress signaling role of cyclin C can be fulfilled within the nucleus by de-repression of stress response genes, referred to here as canonical or a day job function. We summarize the current knowledge on cyclin C biology including its dual role in eliciting stress signaling while highlighting potential implications relevant to cancer and cancer therapy
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