The Less Known Cyclins: History
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Adrian Krajewski

Cyclins belong to a group of proteins that are cyclically produced and destructed in a cell. Cyclins are a family of proteins that are a key component of the cell cycle regulating system, which level of expression depends on the phase of the cycle.

  • cyclins
  • cell cycle
  • cancer

1. Introduction

The cell cycle is a process in which a series of biophysical and biochemical changes take place. In cell division, two daughter cells are produced and contain identical genetic material as the parent cell. Progress of the cell cycle is determined by the activity of two classes of regulatory proteins: cyclins and cyclin-dependent kinases (Cdks). Cyclins belong to the group of proteins that are necessary for the proper course of all life stages [1]. The main feature of cyclins is its variable concentrations depending on the phase of the cell cycle (Figure 1). In turn, Cdks are present in the cells throughout all cell cycle phases in an inactive form. Their activation is a result of the connection with the appropriate cyclin. Cyclin/Cdk complex affects the length of individual phases, and also determines whether the cell can enter the next phase. The division into mitotic cyclins and a group of G1 phase cyclins are commonly known. Mitotic cyclins include A and B cyclins, while D and E can be assigned as G1 phase cyclins. In turn, the group of less known cyclins includes C, F, G, H, I, J, K, L, M, O, T and Y cyclins. Cyclins have been known as regulators of the cell cycle for a long time, but recent studies also indicate their important role in the process of carcinogenesis. Maintaining the correct expression of cyclins is crucial not only for normal cell proliferation but also plays a significant role in other cellular processes like transcription, DNA repair and cell differentiation. Disruption of these proteins may lead to abnormal cell proliferation and cancer progression, thus cancer is often called a cell cycle disease [2][3]. Dysregulation of the cell’s life cycle is one of the most common variables during tumor development. Cell cycle progression is a highly ordered and strictly regulated process involving many control points, which disruption may result in uncontrolled cell divisions. Therefore, understanding the molecular mechanisms of the cell-division cycle abnormalities in cancer may provide important information on how normal cells undergo malignant transformation and how new treatment strategies can be designed [4].

Applsci 11 02320 g001 550

Figure 1. Expression patterns of the less-known cyclins. The data were obtained from endoDB (a database of endothelial cell transcriptomics data). The graphs show cyclin expression in human lung tumor endothelial cells. (A) cyclin C (B) cyclin F (C) cyclin G1 and G2 (D) cyclin H (E) cyclin I (F) cyclin J (G) cyclin K (H) cyclin L (I) cyclin M (J) cyclin O (K) cyclin T1 and cyclin T2 (L) cyclin Y.

2. Cyclin C

Cyclin C is a protein encoded by the CCNC gene, which is located in position 16.2 on chromosome 6. The cyclin belongs to the subfamily of transcriptional cyclins. It was first isolated as a G1 growth factor along with cyclins D and E [5][6]. It consists of 283 amino acids, while its molecular weight is 33.2 kDa [5][6]. Cyclin C contains two 5 α-helix cyclin boxes. It has no additional carboxyl and amino α-helical regions on the C-terminal domain. The N-terminal domain is not included in the α-helix cyclin box and is mobile. Human cyclin C binds to Cdk8 through HC α-helix and activates it [7].

3. Cyclin F

Cyclin F with a molecular weight of 87 kDa is the largest cyclin. It is a cell cycle protein that in humans is encoded by the CCNF gene located in position 16p13.3. It was first identified in 1994 by Bai et al., 1994 [8] and isolated as a suppressor of the G1/S phase transition deficiency of Saccharomyces cerevisiae CDC4 mutant. Cyclin F is the closest relative to the mitotic cyclins: A and B in terms of expression and structure [8][9]. It also has features common to all cyclins, such as richness in proline, glutamic acid, serine and threonine (PEST) region, the abundance of protein, mRNA level dependent on cell cycle stage and ability to control the cell cycle progression [10]. Cyclin F is expressed in all human tissues at different concentrations depending on the cell cycle stage. In most cells, it shows subcellular localization, mainly in the nucleus (in the S and G2 phases), while in the others occurs only in the cytoplasm (mainly in the G2 phase) [8]. The pattern of expression is very similar to cyclin A. The level of cyclin F begins to increase in the S phase and reaches its peak during the G2 phase. However, it does not bind or activate any of the known Cdks. Cyclin F also differs from other cyclins by its ability to monitor and regulate the cell cycle even without activation [11].

Cyclin F is a unique cyclin because it contains not only the cyclin domain but also the F-box region. This domain is necessary for the binding of S-phase kinase-associated protein 1 (Skp1). It is the component of the ubiquitin ligase protein machinery Skp1-Cul1-F-box (SCF). Skp1 also binds Cullin 1 (Cul1) and RING-box protein 1 (RBX1) to assemble a functional SCF complex. Moreover, RBX1 recruits regulatory protein E2 (E2) for the ubiquitination of target substrates. While other cyclins use the catalytic subunit of Cdk to phosphorylate target substrates, cyclin F uses the F-box domain to promote the ubiquitination of target substrates [10][11].

4. Cyclin G

The G type cyclin may be divided into two types [12]. The first is cyclin G1 encoded by the CCNG1 gene, with molecular weight 34 kDa [13]. The second is cyclin G2 encoded by CCNG2, with a molecular weight of 40 kDa [14]. G-type cyclins are able to interact with several proteins from the cyclin-dependent kinase family, such as Cdk2 and Cdk4, but also with serine/threonine-protein phosphatase PP2A-2 catalytic (PP2A) and regulatory subunits (WDB). G-type cyclins (G1 and G2) are crucial factors for tissue differentiation [12]. Cyclin G1 was first identified as one of the first targets of p53 and interacts with several cell cycle regulators, including Mdm2, ADP ribosylation factors (ARF) and Rb [15][16].

5. Cyclin H

Cyclin H is a cell cycle protein encoded by the CCNH gene. Its main function is the activation of Cdk7. The interaction between Cdk7 and cyclin H is stabilized by phosphorylation of Cdk7 in its activation segment. However, the complex may also be stabilized by Mat1 [17][18]. Cyclin H together with Cdk7 and Mat1 forms the structure of Cdk activating kinase (CAK), which is a member of the Cdk family and acts as a positive regulator of Cdk1, Cdk2, Cdk4 and Cdk6 through threonine phosphorylation [19].

6. Cyclin I

Cyclin I is encoded by the CCNI gene localized in position 21.1 on the human chromosome 4. The protein consists of 377 amino acids with a total molecular weight of 42.6 kDa. Cyclin I was first isolated from the human forebrain cortex obtained from an equalized cDNA library. The protein is characterized by the classic cyclin construction, where the N-terminal domain contains a ”cyclin box”, while the PEST sequence is on the C-terminal domain. The protein has significant structural similarity in the N-terminal domain with cyclins G and E, while in C-terminal only with cyclin G. High expression of cyclin I was demonstrated in postmitotic tissues, for example, heart, brain and skeletal muscle. Furthermore, cyclin I binds to the Cdk5 and activates it. In turn, activated Cdk5 plays a key role in postmitotic neurons, through participation in synaptic signaling, neuron development and migration. Moreover, the protein is a pivotal factor in the process of angiogenesis, cell differentiation and survival [20][21].

7. Cyclin J

Cyclin J was originally observed in a yeast two-hybrid screen for embryonic proteins that interact with Cdk2. Although the amino acid sequence of cyclin J most resembles that of the A-type cyclins, it lacks the destruction box and other consensus motifs identified in all mitotic cyclins. Cyclin J is a protein encoded by the CCNJ gene, which is localized in position q24.1 on the human chromosome 10 [22].

8. Cyclin K

Cyclin K is a cell cycle protein. In humans, it is encoded by the CCNK gene, which can be found on chromosome 14q32.2. The protein is the most closely related to human cyclins C and H, which are members of the transcriptional cyclin family. The gene encoding human cyclin K was first isolated as a restoration of cell cycle progression (CPR) due to its participation in shaping the phenotype of the yeast Saccharomyces cerevisiae [23][24]. It also can limit lethality due to the deletion of the G1 cyclin genes, such as Ceroid-Lipofuscinosis, Neuronal 1 (CLN1), Ceroid-Lipofuscinosis, Neuronal 2 (CLN2) and Ceroid-Lipofuscinosis, Neuronal 3 (CLN3) [24]. Cyclin K binds to several cyclin-dependent kinases: Cdk9, Cdk12 and Cdk13, and activates them [25][26].

9. Cyclin L

Cyclin L occurs in two forms: cyclin L1 encoded by the CCNL1 gene located on human chromosome 3 at position q25.31 and cyclin L2 encoded by the CCNL2 gene located on human chromosome 1 at position p36.33 [27]. Cyclin L is the first example of cyclin, which on the N-terminal domain contains a cyclin box, while on the C-terminal domain, the domain rich in alternating arginine and serine residues (RS domain), which is characteristic for serine and arginine-rich (SR) proteins. The RS domain mainly participates in RNA splicing, processing and transport. In terms of the structure, cyclin L is most similar to cyclin K [28][29].

10. Cyclin M

Encoded by the CCNM gene, cyclin M is characterized by strong homology in sequence to the transcriptional cyclin L [30]. This recently discovered cyclin binds and activates Cdk10. In normal cells, cyclin M together with Cdk10 plays an important role in the ciliogenesis process. As was confirmed by Guen et al., 2017 [31] cycM-Cdk10 regulates ciliogenesis by modulating actin dynamics. Actin network reorganization occurs through phosphorylation of protein kinase N2 (PKN2) and activation of the RhoA pathway. The cyclin M and Cdk10 complex bind to the N-terminal domain of PKN2, which is responsible for binding to RhoA. The phosphorylation of two residues, T121 and T124, promotes the binding and stabilization of RhoA, resulting in actin polymerization and repression of primary cilia formation [31][32].

11. Cyclin O

Cyclin O encoded by the CCNO gene is a protein whose molecular weight is 38 kDa. The gene encoding cyclin O is located on the long arm of chromosome 5 at position q11.2. Cyclin O mostly resembles the A- and B-type cyclins. It binds to Cdk1 and Cdk2, which leads to their activation. Cyclin O downregulation blocks the caspase activation [33].

12. Cyclin T

Cyclin T exists in two forms: cyclin T1 encoded by the CCNT1 gene and cyclin T2 encoded by CCNT2. In turn, cyclin T2 may be divided into cyclin T2a and T2b, which is the result of alternative splicing. Cyclin T in the N-terminal domain contains the "cyclin box" domain, which binds to the Cdk9 kinase and the C-terminal domain with PEST [34][35][36]. Similar to cyclin H, the level of cyclin T does not fluctuate during the cell cycle, suggesting that it performs functions that are not specific to the cell cycle. The mRNAs of cyclin T1 and T2 occur in all human tissues. It should be noted that tissues of mesenchymal origin, such as connective tissue, skeletal muscle, myocardial cells, adipocytes, chondrocytes and endothelial cells, and blood and lymphoid tissues, show high levels of cyclin T1 expression. In turn, T2a cyclin is extensively expressed in all cell types, although higher levels occur in some terminally differentiated tissues, such as muscle, blood, lymphoid and connective tissues [35][36][37].

This entry is adapted from the peer-reviewed paper 10.3390/app11052320

References

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