Once cells have duplicated their DNA, Cdk1 becomes activated by A- and B-type cyclins, promoting cellular processes such as centrosome maturation and separation, chromosome condensation and mitotic entry after nuclear envelope breakdown [ 3 ]. This simplified view is obscured owing to multiple non-consensus interactions between CDKs and cyclins and compensatory roles [ 6 ]. For instance, when Cdk4 and Cdk6 are absent, Cdk2 can bind to D-type cyclins [ 27 ].
Cdk1 can also bind to cyclin E or cyclin D in the absence of Cdk2 or Cdk4, respectively [ 9 ], suggesting a scenario reminiscent of the yeast cell cycle in which Cdc28 is sufficient to induce all cell-cycle transitions by interacting with different cyclins [ 6 ]. An overview of CDK functions in the cell. Each CDK in orange boxes is shown in a complex with its major partner green - for clarity, only a few substrates are depicted.
Most CDKs function in the nucleus orange background , whereas a few family members are attached to the cell membrane or display cytoplasmic activities blue background. Classical cell cycle CDKs - Cdk4, Cdk6, Cdk2 and Cdk1 - regulate the transitions through the different phases of the cell-division cycle. These activities are at least partially mediated by the control of multiple transcription factors TFs or regulatory elements such as the retinoblastoma protein Rb.
The Mediator complex is specifically regulated by Cdk8 or the highly related Cdk Cdk5 displays many functions in the cell, but it is better known for its function in the control of neuron-specific proteins such as Tau. The members of the Cdk14 subfamily, such as Cdk14 itself or Cdk16, are activated at the membrane by cyclin Y and also participate in many different pathways, such as Wnt-dependent signaling or signal transduction in the primary cilium. It is important to note that, for clarity, many interactions between CDKs and other partners, substrates or cellular processes are not shown - for instance, Cdk1 can bind to other cyclins and can also phosphorylate more than substrates during mitotic entry that are not indicated here.
Despite its similarity to other cell-cycle-related Cdks, Cdk5 is the prototype of what are termed atypical CDKs. This kinase is activated by the non-cyclin proteins Cdk5R1 p35 or Cdk5R2 p39 , and phosphorylation in the T-loop is not required for its activation [ 28 , 29 ]. Although Cdk5 is expressed in multiple cell types, its activity is thought to be more restricted owing to the expression of its activators p35 and p39 in terminally differentiated cells such as neurons [ 28 ].
However, in addition to its crucial functions in neuronal biology, Cdk5 plays multiple roles in gene expression, differentiation, angiogenesis and senescence, among others [ 5 , 28 , 29 ]. Interestingly, the Cdk5 activators carry an amino-terminal myristoylation motif that is required for their membrane targeting Figure 4.
Like Cdk5, Cdk16 requires no T-loop phosphorylation, suggesting that cyclin Y, like p35, tightly interacts with the activation loop, alleviating the need for an activating phosphorylation [ 13 ]. Cdk16 also binds to cyclin Y, and these complexes phosphorylate several proteins, including N-ethylmaleimide-sensitive factor NSF for the control of exocytosis [ 30 ], and are essential for spermatogenesis [ 22 ].
The partner CDKs of cyclin Y display overlapping roles as knockdown of individual CDKs in Xenopus embryos failed to produce a phenotype, whereas depletion of cyclin Y and its highly related homolog cyclin-Y-like resulted in a Wnt loss-of-function phenotype [ 31 ]. In fact, cyclin Y reaches maximum levels at G2-M phase of the cell cycle and is degraded in a ubiquitin-dependent manner, similarly to mitotic cyclins, suggesting a crucial role for the cyclin-Y-Wnt pathway during cell division [ 12 ].
It is interesting to note that CDKs and cyclins of this subfamily, such as Cdk17 or cyclin Y, are highly conserved, at levels similar to Cdk1 or cyclin B [ 13 ]. In most cases, the cellular relevance of many Cdk5-subfamily members remains to be established. The CTD consists of multiple repeats of an evolutionarily conserved heptapeptide possessing the consensus sequence Tyr-Ser-Pro-Thr-Ser-Pro-Ser, with the number of repeats varying among different organisms, ranging from 26 repeats in yeast to 52 in mammals.
The CTD is the target of multiple posttranslational modifications, including phosphorylation, generating a complex regulatory code known as the CTD code. The CTD regulates the cycling of RNAPII between a hypophosphorylated form, able to enter the preinitiation complex, and a hyperphosphorylated form capable of processive elongation of the transcript [ 32 ].
Cdk7 is a member of the ten-subunit general transcription factor TFIIH b that phosphorylates Ser5 and Ser7 of the heptad during initiation and promoter clearance [ 33 , 34 ].
Cdk7 also phosphorylates and activates Cdk9, thus promoting downstream events [ 34 ]. Cdk9 binds to T-type cyclins T1 and T2 as a subunit of the positive transcription elongation factor b P-TEFb that stimulates elongation. Although Cdk9 was thought to be the major Ser2 kinase required for efficient elongation, recent data suggest that this requirement is mediated by a second substrate of Cdk9, the elongation factor subunit Spt5, whose Cdk9-dependent phosphorylation relieves the early pausing step [ 35 ].
Recent studies in Drosophila and human cells suggest that Cdk12, in complex with cyclin K, is the yeast Ctk1 ortholog responsible for most of the Ser2 phosphorylation at the CTD and especially the phosphorylation at promoter-distal regions [ 36 , 37 ]. Depletion of Cdk12 resulted in defective Ser2 phosphorylation at a subset of genes - mostly long and complex ones - but not a change in the rate of global transcription. Cdk12 is specifically required for the transcription of genes involved in the response to DNA damage, establishing a new link between the transcriptional machinery and cell-cycle regulation [ 37 ].
Cdk1 can also phosphorylate the CTD, and this activity is thought to inhibit transcription, although its physiological relevance has not been established. Although the control of dephosphorylation is not well understood, several CDK-counteracting phosphatases such as Cdc14 are likely to be involved [ 38 , 39 ].
Cdk8 and its closely related family member Cdk19 associate with C-type cyclins as part of the multi-subunit Mediator complex Figure 4 [ 15 ]. This complex functions as a bridge linking gene-specific activators to the general RNAPII transcription machinery at the promoter, thus influencing nearly all stages of transcription and coordinating these events with changes in chromatin organization. The Cdk8 module responds to several intracellular signaling pathways, and it is commonly associated with repression of transcription, although it can also activate transcription [ 15 ].
Cdk8 has multiple targets and phosphorylates several transcription factors, affecting their stability and activity. Cdk8 also modulates Cdk7 activity by phosphorylating cyclin H, thus impeding Cdk7 activity and inhibiting initiation of transcription [ 33 ]. Finally, Cdk19 associates with similar Mediator complexes, although these complexes are likely to possess a specificity that is yet to be established [ 41 ]. Cdk11 binds to L-type cyclins and participates in the coordination between transcription and RNA processing, particularly alternative splicing [ 42 ].
In budding yeast, Cdk11 has been shown to be a crucial factor for the interaction of the Cdk8 module with the Mediator complex through phosphorylation of conserved residues of the Med27 and Med4 Mediator subunits Figure 4 [ 43 ].
Cdk11 also participates in many other pathways, such as hormone receptor signaling or autophagy [ 44 — 46 ]. The short isoform of Cdk11, Cdk11 p58 , is specifically expressed at G2-M, and its kinase activity is required for duplication of the centrioles, spindle dynamics and sister chromatid cohesion at centromeres during mitosis [ 47 — 49 ].
Cdk10 is activated by cyclin M, a cyclin mutated in STAR syndrome, a developmental abnormality characterized by toe syndactyly, telecanthus and anogenital and renal malformations [ 50 ]. Cdkcyclin-M phosphorylates Ets2, promoting its degradation by the proteasome [ 50 ].
In the insect Helicoverpa armigera , Cdk10 modulates gene transcription by steroid hormones by promoting the interaction between heat-shock proteins and the ecdysone receptor EcRB1 [ 51 ]. It is abundantly clear that the CDK family is central to multiple signaling pathways controlling transcription and cell-cycle progression. CDKs probably originated as a system to modulate cell-cycle-promoting activity in response to various cellular scenarios.
Over the course of evolution, both CDK and cyclin gene families have independently undergone a significant number of functional specializations [ 7 ].
Many of the interactions between specific mammalian CDKs and cyclins have been reported in vitro. However, the biochemical promiscuity in CDK-cyclin interactions makes it difficult to evaluate properly the in vivo physiological relevance of specific CDK-cyclin complexes. Cdk5 can also bind to D-type cyclins, although to what extent these complexes are active or relevant in vivo is not clear.
The situation is even more complex for the lesser-known family members for which there are no current in vivo data [ 2 ]. Although the comparison of the yeast CDKs has promoted the convenient division between transcriptional and cell-cycle activities, the multiple interactions between these two activities in higher eukaryotes makes it difficult to maintain this simple classification.
First, transcription and cell-cycle progression cannot be opposed as these processes function at different layers in cell biology. Arguably, transcription is a major regulatory pathway required for cell-cycle entry. Major cell-cycle-related kinases such as Cdk4 and Cdk6 mostly function by phosphorylating transcription regulators such as Rb or Smads [ 3 , 25 ], and the archetypal cell-cycle kinase Cdk1 also phosphorylates multiple transcription factors and epigenetic modulators Figure 4 [ 5 ].
Finally, a single CDK can have separate cell-cycle-related and transcriptional activities. As a consequence of their importance in multiple processes, CDKs are frequently mutated or deregulated in disease. A classic example is the almost universal deregulation of the CDK-cyclin-Rb pathway in cell-cycle entry during malignant transformation [ 25 ]. Other members of the CDK family can also be considered as interesting targets for therapeutics in cancer or other diseases.
Cdk5 displays multiple roles in neurodegenerative diseases [ 28 ] and in other tissues with relevance to diabetes, cardiovascular disease or cancer [ 29 ]. Cdk8 exhibits copy-number gains in colon cancers, and recently it has been characterized as a coactivator of the beta-catenin pathway in colon cancer cell proliferation [ 60 , 61 ]. Cdk14 confers motility advantages and metastatic potential in hepatocellular carcinoma motility and metastasis [ 64 , 65 ].
Finally, as indicated above, cyclin Y kinases regulate the Wnt pathway [ 31 ], providing new therapeutic opportunities that are yet to be explored. Hence, it seems very likely that new targets within the CDK family will be explored in the near future for therapy of cancer or other diseases. Cyclins are a large family of approximately 30 proteins varying in mass from 35 to 90 kDa. Many cyclins have two cyclin boxes, one amino-terminal box for binding to CDKs, and a carboxy-terminal box that is usually required for the proper folding of the cyclin molecule.
In general, cyclins show less sequence similarity than the CDKs. Cyclin D and cyclin E clades partners of Cdk1 and Cdk4 subfamilies have undergone lineage-specific expansion and specialization in metazoa and plants [ 7 ]. This complex plays a role in the coordination and progression of mitosis, likely as a consequence of the redistribution of CAK within different cell compartments during the late nuclear-division steps [ 67 ]. Consistent with this hypothesis is the observation that mice lacking all three D-type cyclins display severe defects of the hematopoietic stem cells Kozar et al.
Clearly, this hypothesis is attractive from a therapeutic point of view, but considerable work in cell culture and animal models will be required to determine the exact and discrete roles of G1 cyclin and cdk functions in development and cancer. Mammary Gland Biol. Neoplasia , 9 , 67— Cell Cycle , 4 , [Epub ahead of print]. Cell Biol. Cancer , 57 , — Oncogene , 10 , — Bharadwaj R and Yu H.
Oncogene , 23 , — Cancer Inst. Cell , 6 , — Oncogene , 8 , — Brain Pathol. Science , , — USA , 95 , — Cancer Lett. Genes Dev. Blood , 85 , — Cancer Cell. Oncogene , 22 , — Cancer Res.
Cell , 97 , — USA , 98 , — Cell , , — Cancer , 69 , 92— Oncogene , 17 , — Acta Oncol. Herwig S and Strauss M. Hirai H and Sherr CJ. Inoue K and Sherr CJ. Anticancer Res. Oncogene , 6 , — Malumbres M and Barbacid M. Cancer , 1 , — Massague J. Nature , , — Oncogene , 11 , — Morgan DO. Cell Dev. Motokura T and Arnold A. Murray AW. Nevins JR. Acta , , 73— Pagano M and Jackson PK. Oncogene , 21 , — Rajagopalan H and Lengauer C. Ren S and Rollins BJ. Blood , 98 , — Sherr CJ.
EMBO J. Tetsu O and McCormick F. Cancer Cell , 3 , — Cell , 8 , — Cancer Biol. Tong W and Pollard JW. Laryngoscope , , — Cancer , 80 , — Weinberg RA. Cell , 81 , — Oncogene submitted.
Oncogene , 18 , 19— Cyclins bind to Cdks, activating the Cdks to phosphorylate other molecules. Cyclins are named such because they undergo a constant cycle of synthesis and degradation during cell division. When cyclins are synthesized, they act as an activating protein and bind to Cdks forming a cyclin-Cdk complex.
This complex then acts as a signal to the cell to pass to the next cell cycle phase. Eventually, the cyclin degrades, deactivating the Cdk, thus signaling exit from a particular phase. There are two classes of cyclins: mitotic cyclins and G1 cyclins. G1 cyclins bind to Cdk proteins during G1.
Once bound and activated, the Cdk signals the cell's exit from G1 and entry into S phase. When the cell reaches an appropriate size and the cellular environment is correct for DNA replication, the cyclins begin to degrade. G1 cyclin degradation deactivates the Cdk and leads to entry into S phase. Mitotic cyclins accumulate gradually during G2. Once they reach a high enough concentration, they can bind to Cdks.
0コメント