Cyclin-dependent kinase complex

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The structure of the Cdk2-cyclin A-p27 complex, as determined by X-ray crystallography, reveals that the inhibitor p27 (red) stretches across the top of the cyclin-Cdk complex. Only the amino-terminal region of p27 is shown in the structure. The amino- terminal end of this fragment contains an RXL motif that interacts with the hydrophobic patch of cyclin A. The carboxy-terminal end of the p27 fragment interacts extensively with the beta sheet of Cdk2, causing extensive disruptions to its structure; p27 also inserts into the ATP-binding site of Cdk2 and directly inhibits ATP binding. (PDB 1jsu) Structure of Cdk2-cyclin A-p27.pdf
The structure of the Cdk2–cyclin A–p27 complex, as determined by X-ray crystallography, reveals that the inhibitor p27 (red) stretches across the top of the cyclin–Cdk complex. Only the amino-terminal region of p27 is shown in the structure. The amino- terminal end of this fragment contains an RXL motif that interacts with the hydrophobic patch of cyclin A. The carboxy-terminal end of the p27 fragment interacts extensively with the beta sheet of Cdk2, causing extensive disruptions to its structure; p27 also inserts into the ATP-binding site of Cdk2 and directly inhibits ATP binding. (PDB 1jsu)

A cyclin-dependent kinase complex (CDKC, cyclin-CDK) is a protein complex formed by the association of an inactive catalytic subunit of a protein kinase, cyclin-dependent kinase (CDK), with a regulatory subunit, cyclin. [1] Once cyclin-dependent kinases bind to cyclin, the formed complex is in an activated state. Substrate specificity of the activated complex is mainly established by the associated cyclin within the complex. Activity of CDKCs is controlled by phosphorylation of target proteins, as well as binding of inhibitory proteins. [2]

Contents

Structure and Regulation

Cyclin binding alone causes partial activation of Cdks, but complete activation also requires activating phosphorylation by CAK. In animal cells, CAK phosphorylates the Cdk subunit only after cyclin binding, and so the two steps in Cdk activation are usually ordered as shown here, with cyclin binding occurring first. Budding yeast contains a different version of CAK that can phosphorylate the Cdk even in the absence of cyclin, and so the two activation steps can occur in either order. In all cases, CAK tends to be in constant excess in the cell, so that cyclin binding is the rate-limiting step in Cdk activation. Two steps in Cdk activation.pdf
Cyclin binding alone causes partial activation of Cdks, but complete activation also requires activating phosphorylation by CAK. In animal cells, CAK phosphorylates the Cdk subunit only after cyclin binding, and so the two steps in Cdk activation are usually ordered as shown here, with cyclin binding occurring first. Budding yeast contains a different version of CAK that can phosphorylate the Cdk even in the absence of cyclin, and so the two activation steps can occur in either order. In all cases, CAK tends to be in constant excess in the cell, so that cyclin binding is the rate-limiting step in Cdk activation.
The central substrate-recognition site on Cdks lies in the active-site T-loop, which interacts with the SPXK consensus sequence that contains the phosphorylation site (see Figure 3-12). An RXL motif in some substrates interacts with the hydrophobic patch on the cyclin, thereby enhancing the rate of phosphorylation. The presence of a phosphate-binding pocket on the accessory subunit Cks1 may facilitate interactions with targets that contain multiple phosphorylation sites. Substrate-targeting sites on cyclin-Cdk complexes.pdf
The central substrate-recognition site on Cdks lies in the active-site T-loop, which interacts with the SPXK consensus sequence that contains the phosphorylation site (see Figure 3-12). An RXL motif in some substrates interacts with the hydrophobic patch on the cyclin, thereby enhancing the rate of phosphorylation. The presence of a phosphate-binding pocket on the accessory subunit Cks1 may facilitate interactions with targets that contain multiple phosphorylation sites.

The structure of CDKs in complex with a cyclin subunits (CDKC) has long been a goal of structural and cellular biologists starting in the 1990s when the structure of unbound cyclin A was solved by Brown et al. and in the same year Jeffery et al. solved the structure of human cyclin A-CDK2 complex to 2.3 Angstrom resolution. [3] Since this time, many CDK structures have been determined to higher resolution, including the structures of CDK2 and CDK2 bound to a variety of substrates, as seen in Figure 1. High resolution structures exist for approximately 25 CDK-cyclin complexes in total within the Protein Data Bank. [4] Based on function, there are two general populations of CDK-cyclin complex structures, open and closed form. The difference between the forms lies within the binding of cyclin partners where closed form complexes have CDK-cyclin binding at both the C and N-termini of the activation loop of the CDK, whereas the open form partners bind only at the N-terminus. Open form structures correspond most often to those complexes involved in transcriptional regulation (CDK 8, 9, 12, and 13), while closed form CDK-cyclin complex are most often involved in cell cycle progression and regulation (CDK 1, 2, 6). These distinct roles, however, do not significantly differ with the sequence homology between the CDK components. In particular, among these known structures there appear to be four major conserved regions: a N-terminal Glycine-rich loop, a Hinge Region, an αC-helix, and a T-loop regulation site. [4]

Activation Loop

The activation loop, also referred to as the T-loop, is the region of CDK (between the DFG and APE motifs in many CDK) [4] that is enzymatically active when CDK is bound to its function-specific partner. In CDK-cyclin complexes, this activation region is composed of a conserved αL-12 Helix and contains a key phosphorylatable residue (usually Threonine for CDK-cyclin partners, but also includes Serine and Tyrosine) that mediates the enzymatic activity of the CDK. It is at this essential residue (T160 in CDK2 complexes, T177 in CDK6 complexes) that enzymatic ATP-phosphorylation of CDK-cyclin complexes by CAK (cyclin activating kinase, referring to the CDK7-Cyclin H complex in human cells) takes place. After the hydrolysis of ATP to phosphorylate at this site, these complexes are able to complete their intended function, the phosphorylation of cellular targets. It is important to note that in CDK 1, 2 and 6, the T-loop and a separate C-terminal region are the major sites of cyclin binding in the CDK, and which cyclins are bound to each of these CDK is mediated by the particular sequence of the activation site T-loop. These cyclin binding sites are the regions of highest variability in CDKs despite relatively high sequence homology surrounding the αL-12 Helix motif of this structural component. [4]

Glycine-rich region

The glycine-rich loop (Gly-rich loop) as seen in residues 12-16 in CDK2 encodes a conserved GXGXXG motif across both yeast and animal models. The regulatory region is subject to differential phosphorylation at non-glycine residues within this motif, making this site subject to Wee1 and/or Myt1 inhibitory kinase phosphorylation and Cdc25 de-phosphorylation in mammals. This reversible phosphorylation at the Gly-rich loop in CDK2 occurs at Y15, where activity has been further studied. Study of this residue has shown that phosphorylation promotes a conformational change that prevents ATP and substrate binding by steric interference with these necessary binding sites in the activation loop of the CDK-cyclin complexes. This activity is aided by the notable flexibility that the Gly-rich loop has within the structure of most CDK allowing for its rotation toward the activation loop to have a significant effect on reducing substrate affinity without major changes in the overall CDK-cyclin complex structure. [3] [5]

Hinge Region

The conserved hinge region of CDK within eukaryotic cells acts as an essential bridge between the Gly-rich loop and the activation loop. CDK are characterized by a N-terminal lobe that is primarily twisted beta-sheet connected via this hinge region to an alpha helix dominated C-terminal lobe. In discussion of the T-loop and the Gly-rich loop, it is important to note that these regions, which must be able to spatially interact in order to carry out their biochemical functions, lie on opposite lobes of the CDK itself. Thus, this hinge region, which can vary in length slightly between CDK type and CDK-cyclin complex, connects essential regulatory regions of the CDK by connecting these lobes, and plays key roles in the resulting structure of CDK-cyclin complexes by properly orienting ATP for easy catalysis of phosphorylation reactions by the assembled complex. [3] [4]

αC-Helix

The αC-Helix region is highly conserved across many of the mammalian kinome (family of kinases). Its main responsibility is to maintain allosteric control of the kinase active site. This control manifests in CDK-cyclin complexes by specifically preventing CDK activity until its binds to its partner regulator (i.e. cyclin or other partner protein). This binding causes a conformational change in the αC-Helix region of the CDK and allows for it to be moved from the active site cleft and completes the initial process of T-loop activation. Given that this region is so conserved across the protein superfamily of kinases, this mechanism where the αC-Helix has been shown to fold out of the N-terminal lobe of the kinase, allowing for increased access to the αL-12 Helix that lies within the T-loop, is considered a potential target for drug development. [6]

The cell cycle

Yeast cell cycle

Although these complexes have a variety functions, CDKCs are most known for their role in the cell cycle. Initially, studies were conducted in Schizosaccharomyces pombe and Saccharomyces cerevisiae (yeast). S. pombe and S. cerevisiae are most known for their association with a single Cdk, Cdc2 and Cdc28 respectively, which complexes with several different cyclins. [7] Depending on the cyclin, various portions of the cell cycle are affected. For example, in S. pombe, Cdc2 associates with Cdk13 to form the Cdk13-Cdc2 complex. In S. cerevisiae, the association of Cdc28 with cyclins, Cln1, Cln2, or Cln3, results in the transition from G1 phase to S phase. Once in the S phase, Cln1 and Cln2 dissociates with Cdc28 and complexes between Cdc28 and Clb5 or Clb6 are formed. In G2 phase, complexes formed from the association between Cdc28 and Clb1, Clb2, Clb3, or Clb4, results in the progression from G2 phase to M (Mitotic) phase. These complexes are present in early M phase as well. [2] See Table 1 for a summary of yeast CDKCs.

Table 1. CDKCs Associated with Cell Cycle Phases in Yeast
CDKCyclinCell Cycle Phase
Cdc2 (S. pombe)Cdc13G2 to M phase transition; early M phase
Cdc28 (S. cerevisiae)Cln1, Cln2G1 to S phase transition
Cdc28Clb5, Clb6S phase
Cdc28Clb1, Clb2, Clb3, Clb4G2 to M phase transition; early M phase

From what is known about the complexes formed during each phase of the cell cycle in yeast, proposed models have emerged based on important phosphorylation sites and transcription factors involved. [7] [8]

Mammalian cell cycle

Using the information discovered through yeast cell cycle studies, significant progress has been made regarding the mammalian cell cycle. It has been determined that the cell cycles are similar and CDKCs, either directly or indirectly, affect the progression of the cell cycle. As previously mentioned, in yeast, only one cyclin-dependent kinase (CDK) is associated with several different cyclins. However, in mammalian cells, several different CDKs bind to various cyclins to form CDKCs. For instance, Cdk1 (also known as human Cdc2), the first human CDK to be identified, associates with cyclins A or B. CyclinA/B-Cdk1 complexes drive the transition between G2 phase and M phase, as well as early M phase. Another mammalian CDK, Cdk2, can form complexes with cyclins D1, D2, D3, E, or A. Cdk4 and Cdk6 interact with cyclins D1, D2, and D3. [9] Studies have indicated that there is no difference between CDKCs cyclin D1-Cdk4/6, therefore, any unique properties can possibly be linked to substrate specificity or activation. [1] While levels of CDKs remain fairly constant throughout the cell cycle, cyclin levels fluctuate. The fluctuation controls the activation of the cyclin-CDK complexes and ultimately the progression throughout the cycle. [10] See Table 2 for a summary of mammalian cell CDKCs involved in the cell cycle.

Table 2. CDKCs Associated with Cell Cycle Phases in Mammalian Cells [4]
CDKCyclinCell Cycle PhaseNon-Cyclin Partner Proteins
Cdk1 (Cdc2)Cyclins A and BG2 to M phase transition; early M phaseCks1 and Cks2
Cdk2Cyclins D1, D2, D3G1 phaseKAP, Cks1, p27KIP1, and Spy-1
Cdk2Cyclin EG1 to S phase transitionKAP, Cks1, p27KIP1, and Spy-1
Cdk2Cyclin AS phaseKAP, Cks1, p27KIP1, and Spy-1
Cdk4Cyclins D1, D2, D3G1 phaseHSP90-Cdc37
Cdk6Cyclins D1, D2, D3G1 phasep16INK4A, p19INK4D, and P18INK4C-cyclin K
Cdk8Cyclin C------
Cdk9Cyclin T---Tat, AFF4, and TAR
Cdk12Cyclin K------
Cdk13Cyclin K------
Figure 1. Expression of cyclins A, B, D, and E through the phases of the cell cycle. Cyclin Expression.svg
Figure 1. Expression of cyclins A, B, D, and E through the phases of the cell cycle.

G1 to S phase progression

During late G1 phase, CDKCs bind and phosphorylate members of the retinoblastoma (Rb) protein family. Members of the Rb protein family are tumor suppressors, which prevent uncontrolled cell proliferation that would occur during tumor formation. However, pRbs are also thought to repress the genes required in order for the transition from G1 phase to S phase to occur. When the cell is ready to transition into the next phase, CDKCs, cyclin D1-Cdk4 and cyclin D1-Cdk6 phosphorylate pRB, followed by additional phosphorylation from the cyclin E-Cdk2 CDKC. [11] [12] Once phosphorylation occurs, transcription factors are then released to irreversibly inactivate pRB and progression into the S phase of the cell cycle ensues. [13] The cyclin E-Cdk2 CDKC formed in the G1 phase then aids in the initiation of DNA replication during S phase. [1]

G2 to M phase progression

At the end of S phase, cyclin A is associated with Cdk1 and Cdk2. During G2 phase, cyclin A is degraded, while cyclin B is synthesized and cyclin B-Cdk1 complexes form. Not only are cyclin B-Cdk1 complexes important for the transition into M phase, but these CDKCs play a role in the following regulatory and structural processes: [1]

  • Chromosomal condensation
  • Fragmentation of Golgi network
  • Breakdown of nuclear lamina

Inactivation of the cyclin B-Cdk1 complex through the degradation of cyclin B is necessary for exit out of the M phase of the cell cycle. [1]

Other

Even though the majority of the known CDKCs are involved in the cell cycle, not all kinase complexes function in this manner. Studies have shown other CDKCs, such as cyclin k-Cdk9 and cyclin T1-Cdk9, are involved in the replication stress response, [14] and influence transcription. [15] [16] [17] Additionally, cyclin H-Cdk7 complexes may play a role in meiosis in male germ cells, [18] and has been shown to be involved in transcriptional activities as well. [1] [19]

See also

Related Research Articles

<span class="mw-page-title-main">Cell cycle</span> Series of events and stages that result in cell division

The cell cycle, or cell-division cycle, is the series of events that take place in a cell that causes it to divide into two daughter cells. These events include the duplication of its DNA and some of its organelles, and subsequently the partitioning of its cytoplasm, chromosomes and other components into two daughter cells in a process called cell division.

<span class="mw-page-title-main">Cyclin</span> Group of proteins

Cyclin is a family of proteins that controls the progression of a cell through the cell cycle by activating cyclin-dependent kinase (CDK) enzymes or group of enzymes required for synthesis of cell cycle.

<span class="mw-page-title-main">Cyclin-dependent kinase</span> Class of enzymes

Cyclin-dependent kinases (CDKs) are the families of protein kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved. In fact, yeast cells can proliferate normally when their CDK gene has been replaced with the homologous human gene. CDKs are relatively small proteins, with molecular weights ranging from 34 to 40 kDa, and contain little more than the kinase domain. By definition, a CDK binds a regulatory protein called a cyclin. Without cyclin, CDK has little kinase activity; only the cyclin-CDK complex is an active kinase but its activity can be typically further modulated by phosphorylation and other binding proteins, like p27. CDKs phosphorylate their substrates on serines and threonines, so they are serine-threonine kinases. The consensus sequence for the phosphorylation site in the amino acid sequence of a CDK substrate is [S/T*]PX[K/R], where S/T* is the phosphorylated serine or threonine, P is proline, X is any amino acid, K is lysine, and R is arginine.

<span class="mw-page-title-main">S phase</span> DNA replication phase of the cell cycle, between G1 and G2 phase

S phase (Synthesis phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during S-phase are tightly regulated and widely conserved.

G<sub>2</sub> phase Second growth phase in the eukaryotic cell cycle, prior to mitosis

G2 phase, Gap 2 phase, or Growth 2 phase, is the third subphase of interphase in the cell cycle directly preceding mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated. G2 phase ends with the onset of prophase, the first phase of mitosis in which the cell’s chromatin condenses into chromosomes.

E2F is a group of genes that encodes a family of transcription factors (TF) in higher eukaryotes. Three of them are activators: E2F1, 2 and E2F3a. Six others act as suppressors: E2F3b, E2F4-8. All of them are involved in the cell cycle regulation and synthesis of DNA in mammalian cells. E2Fs as TFs bind to the TTTCCCGC consensus binding site in the target promoter sequence.

<span class="mw-page-title-main">Cell cycle checkpoint</span> Control mechanism in the eukaryotic cell cycle

Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are assessed, with progression through the various phases of the cell cycle occurring only when favorable conditions are met. There are many checkpoints in the cell cycle, but the three major ones are: the G1 checkpoint, also known as the Start or restriction checkpoint or Major Checkpoint; the G2/M checkpoint; and the metaphase-to-anaphase transition, also known as the spindle checkpoint. Progression through these checkpoints is largely determined by the activation of cyclin-dependent kinases by regulatory protein subunits called cyclins, different forms of which are produced at each stage of the cell cycle to control the specific events that occur therein.

Cyclin A is a member of the cyclin family, a group of proteins that function in regulating progression through the cell cycle. The stages that a cell passes through that culminate in its division and replication are collectively known as the cell cycle Since the successful division and replication of a cell is essential for its survival, the cell cycle is tightly regulated by several components to ensure the efficient and error-free progression through the cell cycle. One such regulatory component is cyclin A which plays a role in the regulation of two different cell cycle stages.

<span class="mw-page-title-main">CDK-activating kinase</span>

CDK-activating kinase (CAK) activates the cyclin-CDK complex by phosphorylating threonine residue 160 in the CDK activation loop. CAK itself is a member of the Cdk family and functions as a positive regulator of Cdk1, Cdk2, Cdk4, and Cdk6.

<span class="mw-page-title-main">Cyclin D</span> Member of the cyclin protein family

Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition. Cyclin D protein is anywhere from 155 to 477 amino acids in length.

<span class="mw-page-title-main">Cyclin-dependent kinase 2</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme that in humans is encoded by the CDK2 gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein kinases. This protein kinase is highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, also known as Cdk1 in humans. It is a catalytic subunit of the cyclin-dependent kinase complex, whose activity is restricted to the G1-S phase of the cell cycle, where cells make proteins necessary for mitosis and replicate their DNA. This protein associates with and is regulated by the regulatory subunits of the complex including cyclin E or A. Cyclin E binds G1 phase Cdk2, which is required for the transition from G1 to S phase while binding with Cyclin A is required to progress through the S phase. Its activity is also regulated by phosphorylation. Multiple alternatively spliced variants and multiple transcription initiation sites of this gene have been reported. The role of this protein in G1-S transition has been recently questioned as cells lacking Cdk2 are reported to have no problem during this transition.

<span class="mw-page-title-main">Cyclin-dependent kinase 6</span> Protein-coding gene in the species Homo sapiens

Cell division protein kinase 6 (CDK6) is an enzyme encoded by the CDK6 gene. It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins. The protein encoded by this gene is a member of the cyclin-dependent kinase, (CDK) family, which includes CDK4. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression in the point of regulation named R or restriction point.

CDK7 is a cyclin-dependent kinase shown to be not easily classified. CDK7 is both a CDK-activating kinase (CAK) and a component of the general transcription factor TFIIH.

<span class="mw-page-title-main">Cyclin-dependent kinase inhibitor protein</span> Protein which inhibits cyclin-dependent kinase

A cyclin-dependent kinase inhibitor protein(also known as CKIs, CDIs, or CDKIs) is a protein which inhibits the enzyme cyclin-dependent kinase (CDK) and Cyclin activity by stopping the cell cycle if there are unfavorable conditions, therefore, acting as tumor suppressors. Cell cycle progression is stopped by Cyclin-dependent kinase inhibitor protein at the G1 phase. CKIs are vital proteins within the control system that point out whether the process of DNA synthesis, mitosis, and cytokines control one another. If a malfunction prevents the successful completion of DNA synthesis during the G1 phase, a signal is sent to delay or stop the progression to the S phase. Cyclin-dependent kinase inhibitor proteins are essential in the regulation of the cell cycle. If cell mutations surpass the cell cycle checkpoints during cell cycle regulation, it can result in various types of cancer.

<span class="mw-page-title-main">Cyclin-dependent kinase 1</span> Mammalian protein found in Homo sapiens

Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog is a highly conserved protein that functions as a serine/threonine protein kinase, and is a key player in cell cycle regulation. It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S. pombe, where it is encoded by genes cdc28 and cdc2, respectively. With its cyclin partners, Cdk1 forms complexes that phosphorylate a variety of target substrates ; phosphorylation of these proteins leads to cell cycle progression.

Sic1, a protein, is a stoichiometric inhibitor of Cdk1-Clb complexes in the budding yeast Saccharomyces cerevisiae. Because B-type cyclin-Cdk1 complexes are the drivers of S-phase initiation, Sic1 prevents premature S-phase entry. Multisite phosphorylation of Sic1 is thought to time Sic1 ubiquitination and destruction, and by extension, the timing of S-phase entry.

<span class="mw-page-title-main">Wee1</span> Nuclear protein

Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast Schizosaccharomyces pombe. Wee1 has a molecular mass of 96 kDa and is a key regulator of cell cycle progression. It influences cell size by inhibiting the entry into mitosis, through inhibiting Cdk1. Wee1 has homologues in many other organisms, including mammals.

A series of biochemical switches control transitions between and within the various phases of the cell cycle. The cell cycle is a series of complex, ordered, sequential events that control how a single cell divides into two cells, and involves several different phases. The phases include the G1 and G2 phases, DNA replication or S phase, and the actual process of cell division, mitosis or M phase. During the M phase, the chromosomes separate and cytokinesis occurs.

<span class="mw-page-title-main">G2-M DNA damage checkpoint</span>

The G2-M DNA damage checkpoint is an important cell cycle checkpoint in eukaryotic organisms that ensures that cells don't initiate mitosis until damaged or incompletely replicated DNA is sufficiently repaired. Cells with a defective G2-M checkpoint will undergo apoptosis or death after cell division if they enter the M phase before repairing their DNA. The defining biochemical feature of this checkpoint is the activation of M-phase cyclin-CDK complexes, which phosphorylate proteins that promote spindle assembly and bring the cell to metaphase.

<span class="mw-page-title-main">Cyclin E/Cdk2</span>

The Cyclin E/Cdk2 complex is a structure composed of two proteins, cyclin E and cyclin-dependent kinase 2 (Cdk2). Similar to other cyclin/Cdk complexes, the cyclin E/Cdk2 dimer plays a crucial role in regulating the cell cycle, with this specific complex peaking in activity during the G1/S transition. Once the two cyclin and Cdk subunits are joined together, the complex becomes activated and proceeds to phosphorylate and bind to downstream proteins to ultimately promote cell cycle progression. Although cyclin E can bind to other Cdk proteins, its primary binding partner is Cdk2, and the majority of cyclin E activity occurs when it exists as the cyclin E/Cdk2 complex.

References

  1. 1 2 3 4 5 6 Malumbres M, Barbacid M. Mammalian cyclin-dependent kinases. Trends Biochem. Sci. 2005 Nov;30(11):630-41
  2. 1 2 Lodish H, Baltimore D, Berk A, Zipursky SL, Matsudaira P, Darnell J. 1995. Molecular Cell Biology. 3rd Ed. New York: Scientific American Books
  3. 1 2 3 Kristi Levine, Frederick R Cross, Structuring cell-cycle biology, Structure, Volume 3, Issue 11, 1995, Pages 1131-1134, ISSN 0969-2126, doi : 10.1016/S0969-2126(01)00248-9.
  4. 1 2 3 4 5 6 Wood, D. J., & Endicott, J. A. (2018). Structural insights into the functional diversity of the CDK-cyclin family. Open biology, 8(9), 180112.
  5. ↑ Malumbres: Cyclin-dependent kinases. Genome Biology, 2014, 15:22, doi : 10.1186/gb4184
  6. ↑ Lorenzo Palmieri, Giulio Rastelli, αC helix displacement as a general approach for allosteric modulation of protein kinases, Drug Discovery Today, Volume 18, Issues 7–8, 2013, Pages 407-414, ISSN 1359-6446, doi : 10.1016/j.drudis.2012.11.009.
  7. 1 2 Simon I, Barnett J, Hannett N, Harbison CT, Rinaldi NJ, Volkert TL, Wyrick JJ, Zeitlinger J, Gifford DK, Jaakkola TS, Young RA. Serial regulation of transcriptional regulators in the yeast cell cycle. Cell. 2001 Sep 21;106(6):697-708.
  8. ↑ Barik D, Baumann WT, Paul MR, Novak B, Tyson JJ. A model of yeast cell-cycle regulation based on multisite phosphorylation. Mol Syst Biol. 2010 Aug 24;6:405.
  9. ↑ Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009 Mar;9(3):153-66.
  10. ↑ Vermeulen K, Van Bockstaele DR, Berneman ZN. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif. 2003 Jun;36(3):131-49.
  11. ↑ Mittnacht S. Control of pRB phosphorylation. Curr Opin Genet Dev. 1998 Feb;8(1):21-7.
  12. ↑ Kaelin WG Jr. Functions of the retinoblastoma protein. Bioessays. 1999 Nov;21(11):950-8.
  13. ↑ Lundberg AS, Weinberg RA. Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol Cell Biol. 1998 Feb;18(2):753-61.
  14. ↑ Yu DS, Zhao R, Hsu EL, Cayer J, Ye F, Guo Y, Shyr Y, Cortez D. Cyclin-dependent kinase 9-cyclin K functions in the replication stress response. EMBO Rep. 2010 Nov;11(11):876-82.
  15. ↑ Fu TJ, Peng J, Lee G, Price DH, Flores O. Cyclin K functions as a CDK9 regulatory subunit and participates in RNA polymerase II transcription. J Biol Chem. 1999 Dec 3;274(49):34527-30.
  16. ↑ Yang Z, Zhu Q, Luo K, Zhou Q. The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature. 2001 Nov 15;414(6861):317-22.
  17. ↑ Yu DS, Cortez D. A role for CDK9-cyclin K in maintaining genome integrity. Cell Cycle. 2011 Jan 1;10(1):28-32.
  18. ↑ Kim JM, McGaughy JT, Bogle RK, Ravnik SE. Meiotic expression of the cyclin H/Cdk7 complex in male germ cells of the mouse. Biol Reprod. 2001 May;64(5):1400-8.
  19. ↑ Patel SA, Simon MC. Functional analysis of the Cdk7.cyclin H.Mat1 complex in mouse embryonic stem cells and embryos. J Biol Chem. 2010 May 14;285(20):15587-98.
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