Cyclin-dependent kinase

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Cyclin-dependent kinase
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Tertiary structure of human Cdk2, determined by X-ray crystallography. Like other protein kinases, Cdk2 is composed of two lobes: a smaller amino-terminal lobe (top) that is composed primarily of beta sheet and the PSTAIRE helix, and a large carboxy-terminal lobe (bottom) that is primarily made up of alpha helices. The ATP substrate is shown as a ball-and-stick model, located deep within the active-site cleft between the two lobes. The phosphates are oriented outward, toward the mouth of the cleft, which is blocked in this structure by the T-loop (highlighted in green). (PDB 1hck) Cyclin-dependent kinase structure.pdf
Tertiary structure of human Cdk2, determined by X-ray crystallography. Like other protein kinases, Cdk2 is composed of two lobes: a smaller amino-terminal lobe (top) that is composed primarily of beta sheet and the PSTAIRE helix, and a large carboxy-terminal lobe (bottom) that is primarily made up of alpha helices. The ATP substrate is shown as a ball-and-stick model, located deep within the active-site cleft between the two lobes. The phosphates are oriented outward, toward the mouth of the cleft, which is blocked in this structure by the T-loop (highlighted in green). (PDB 1hck)

Cyclin-dependent kinases (CDKs) are a predominant group of serine/threonine protein kinases involved in the regulation of the cell cycle and its progression, ensuring the integrity and functionality of cellular machinery. These regulatory enzymes play a crucial role in the regulation of eukaryotic cell cycle and transcription, as well as DNA repair, metabolism, and epigenetic regulation, in response to several extracellular and intracellular signals. [1] [2] They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved. [3] [4] The catalytic activities of CDKs are regulated by interactions with CDK inhibitors (CKIs) and regulatory subunits known as cyclins. Cyclins have no enzymatic activity themselves, but they become active once they bind to CDKs. Without cyclin, CDK is less active than in the cyclin-CDK heterodimer complex. [5] [6] CDKs phosphorylate proteins on serine (S) or threonine (T) residues. The specificity of CDKs for their substrates is defined by the S/T-P-X-K/R sequence, where S/T is the phosphorylation site, P is proline, X is any amino acid, and the sequence ends with lysine (K) or arginine (R). This motif ensures CDKs accurately target and modify proteins, crucial for regulating cell cycle and other functions. [7] Deregulation of the CDK activity is linked to various pathologies, including cancer, neurodegenerative diseases, and stroke. [6]

Contents

Evolutionary History

CDKs were initially identified through studies in model organisms such as yeasts and frogs, underscoring their pivotal role in cell cycle progression. These enzymes operate by forming complexes with cyclins, whose levels fluctuate throughout the cell cycle, thereby ensuring timely cell cycle transitions. Over the years, the understanding of CDKs has expanded beyond cell division to include roles in gene transcription integration of cellular signals. [7] [8]

The evolutionary journey of CDKs has led to a diverse family with specific members dedicated to cell cycle phases or transcriptional control. For instance, budding yeast expresses six distinct CDKs, with some binding multiple cyclins for cell cycle control and others binding with a single cyclin for transcription regulation. In humans, the expansion to 20 CDKs and 29 cyclins illustrates their complex regulatory roles. Key CDKs such as CDK1 are indispensable for cell cycle control, while others like CDK2 and CDK3 are not. Moreover, transcriptional CDKs, such as CDK7 in humans, play crucial roles in initiating transcription by phosphorylating RNA polymerase II (RNAPII), indicating the intricate link between cell cycle regulation and transcriptional management. This evolutionary expansion from simple regulators to multifunctional enzymes underscores the critical importance of CDKs in the complex regulatory networks of eukaryotic cells. [7]

Table 1: Cyclin-dependent kinases that control the cell cycle in model organisms [4]
SpeciesNameOriginal nameSize (amino acids)Function
Saccharomyces cerevisiae CDK1Cdc28298All cell-cycle stages
Schizosaccharomyces pombe CDK1Cdc2297All cell-cycle stages
Drosophila melanogaster CDK1Cdc2297M
CDK2Cdc2c314G1/S, S, possibly M
CDK4Cdk4/6317G1, promotes growth
Xenopus laevis CDK1Cdc2301M
CDK2297S, possibly M
Homo sapiens CDK1 Cdc2297M
CDK2 298G1, S, possibly M
CDK4 301G1
CDK6 326G1

Notable People

In 2001, the scientists Leland H. Hartwell, Tim Hunt and Sir Paul M. Nurse were awarded the Nobel Prize in Physiology or Medicine for their discovery of key regulators of the cell cycle. [9]

CDKs and Cyclins in the Cell Cycle

CDK is one of the estimated 800 human protein kinases. CDKs have low molecular weight, and they are known to be inactive by themselves. They are characterized by their dependency on the regulatory subunit, cyclin. The activation of CDKs also requires post-translational modifications involving phosphorylation reactions. This phosphorylation typically occurs on a specific threonine residue, leading to a conformational change in the CDK that enhances its kinase activity. [13] The activation forms a cyclin-CDK complex which phosphorylates specific regulatory proteins that are required to initiate steps in the cell-cycle. [5]

Schematic of CDKs/cyclins the cell cycle. M = Mitosis; G1 = Gap phase 1; S = Synthesis; G2 = Gap phase 2 (Created with BioRender.com). CDKs in cell cycle.png
Schematic of CDKs/cyclins the cell cycle. M = Mitosis; G1 = Gap phase 1; S = Synthesis; G2 = Gap phase 2 (Created with BioRender.com).

In human cells, the CDK family comprises 20 different members that play a crucial role in the regulation of the cell cycle and transcription. These are usually separated into cell-cycle CDKs, which regulate cell-cycle transitions and cell division, and transcriptional CDKs, which mediate gene transcription. CDK1, CDK2, CDK3, CDK4, CDK6, and CDK7 are directly related to the regulation of cell-cycle events, while CDK7 – 11 are associated with transcriptional regulation. [1] Different cyclin-CDK complexes regulate different phases of the cell cycle, known as G0/G1, S, G2, and M phases, featuring several checkpoints to maintain genomic stability and ensure accurate DNA replication. [1] [5] Cyclin-CDK complexes of earlier cell-cycle phase help activate cyclin-CDK complexes in later phase. [4]

Table 2: Cell-cycle CDKs, their cyclin partners, and their functions in the human [1] [6] [5]
CDKCyclin partnerEstablished functions
CDK1 cyclin BM phase transition
CDK2 cyclin AS/G2 transition
CDK2 cyclin EG1/S transition
CDK3 cyclin CG0/G1 and G1/S transitions
CDK4, CDK6 cyclin DG1/S transition. Phosphorylation of retinoblastoma gene product (Rb)
CDK7 cyclin HCAK and RNAPII transcription

CDK Structure and Activation

Cyclin-dependent kinases (CDKs) mainly consist of a two-lobed configuration, which is characteristic of all kinases in general. CDKs have specific features in their structure that play a major role in their function and regulation. [2]

  1. N-terminal lobe (N-lobe): In this part, the inhibitory element known as the glycine-rich G-loop is located. The inhibitory element is found within the beta-sheets in this N-terminal lobe. [4] [2] Additionally, there is a helix known as the C-helix. This helix contains the PSTAIRE sequence in CDK1. This region plays a crucial role in regulating the binding between cyclin-dependent kinases (CDKs) and cyclins. [7] [2]
  2. C-terminal lobe (C-lobe): This part contains α-helices and the activation segment, which extends from the DFG motif (D145 in CDK2) to the APE motif (E172 in CDK2). This segment also includes a phosphorylation-sensitive residue (T160 in CDK2) in the so-called T-loop. The activation segment in the C-lobe serves as a platform for the binding of the phospho-acceptor Ser/Thr region of substrates. [7] [4] [2]

Cyclin Binding

The active site, or ATP-binding site, in all kinases is a cleft located between a smaller amino-terminal lobe and a larger carboxy-terminal lobe. Research on the structure of human CDK2 has shown that CDKs have a specially adapted ATP-binding site that can be regulated through the binding of cyclin. Phosphorylation by CDK-activating kinase (CAK) at Thr160 in the T-loop helps to increase the complex's activity. Without cyclin, a flexible loop known as the activation loop or T-loop blocks the cleft, and the positioning of several key amino acids is not optimal for ATP binding. [2] [14] With cyclin, two alpha helices change position to enable ATP binding. One of them, the L12 helix located just before the T-loop in the primary sequence, is transformed into a beta strand and helps to reorganize the T-loop so that it no longer blocks the active site. The other alpha helix, known as the PSTAIRE helix, is reorganized and helps to change the position of the key amino acids in the active site. [6] [14]

There's considerable specificity in which cyclin binds to CDK. Furthermore, the cyclin binding determines the specificity of the cyclin-CDK complex for certain substrates, highlighting the importance of distinct activation pathways that confer cyclin-binding specificity on CDK1. This illustrates the complexity and fine-tuning in the regulation of the cell cycle through selective binding and activation of CDKs by their respective cyclins. [15] [16]

Cyclins can directly bind the substrate or localize the CDK to a subcellular area where the substrate is found. The RXL-binding site  was crucial in revealing how CDKs selectively enhance activity toward specific substrates by facilitating substrate docking. [17] Substrate specificity of S cyclins is imparted by the hydrophobic batch, which has affinity for substrate proteins that contain a hydrophobic RXL (or Cy) motif. [4] Cyclin B1 and B2 can localize CDK1 to the nucleus and the Golgi, respectively, through a localization sequence outside the CDK-binding region. [4] [16]

Phosphorylation

Cyclin binding alone causes partial activation of Cdks, but complete activation also requires activating phosphorylation by a CAK. In animal cells, CAK phosphorylates the Cdk subunit only after cyclin binding, as shown here. 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. Two steps in Cdk activation.pdf
Cyclin binding alone causes partial activation of Cdks, but complete activation also requires activating phosphorylation by a CAK. In animal cells, CAK phosphorylates the Cdk subunit only after cyclin binding, as shown here. 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.

To achieve full kinase activity, an activating phosphorylation on a threonine adjacent to the CDK's active site is required. [18] The identity of the CDK-activating kinase (CAK) that carries out this phosphorylation varies among different model organisms. The timing of this phosphorylation also varies; in mammalian cells, the activating phosphorylation occurs after cyclin binding, while in yeast cells, it occurs before cyclin binding. CAK activity is not regulated by known cell cycle pathways, and it is the cyclin binding that is the limiting step for CDK activation. [4]

Unlike activating phosphorylation, CDK inhibitory phosphorylation is crucial for cell cycle regulation. Various kinases and phosphatases control their phosphorylation state. For instance, the activity of CDK1 is controlled by the balance between  WEE1 kinases, Myt1 kinases, and the phosphorylation of  Cdc25c phosphatases. Wee1, a kinase preserved across all eukaryotes, phosphorylates CDK1 at Tyr 15. Myt1 can phosphorylate both the threonine (Thr 14) and the tyrosine (Tyr 15). The phosphorylation is performed by Cdc25c phosphatases, by removing the phosphate groups from both the threonine and the tyrosine. [1] [7]  This inhibitory phosphorylation helps preventing cell-cycle progression in response to events like DNA damage. The phosphorylation does not significantly alter the CDK structure, but reduces its affinity to the substrate, thereby inhibiting its activity. For the cell cycle to progress, these inhibitory phosphates must be removed by the Cdc25 phosphatases to reactivate the CDKs. [7]

CDK Inhibitors

A cyclin-dependent kinase inhibitor (CKI) is a protein that interacts with a cyclin-CDK complex to inhibit kinase activity, often during G1 phase or in response to external signals or DNA damage. In animal cells, two primary CKI families exist: the INK4 family (p16, p15, p18, p19) and the CIP/KIP family  (p21, p27, p57). The INK4 family proteins specifically bind to and inhibit CDK4 and CDK6 by D-type cyclins or by CAK, while the CIP/KIP family prevent the activation of CDK-cyclin heterodimers, disrupting both cyclin binding and kinase activity. [6] [7] These inhibitors have a KID (kinase inhibitory domain) at the N-terminus, facilitating their attachment to cyclins and CDKs. Their primary function occurs in the nucleus, supported by a C-terminal sequence that enables their nuclear translocation. [2]

In yeast and Drosophila, CKIs are strong inhibitors of S- and M-CDK, but do not inhibit G1/S-CDKs. During G1, high levels of CKIs prevent cell cycle events from occurring out of order, but do not prevent transition through the Start checkpoint, which is initiated through G1/S-CDKs. Once the cell cycle is initiated, phosphorylation by early G1/S-CDKs leads to destruction of CKIs, relieving inhibition on later cell cycle transitions. [4] In mammalian cells, the CKI regulation works differently. Mammalian protein p27 (Dacapo in Drosophila) inhibits G1/S- and S-CDKs but does not inhibit S- and M-CDKs. [2]

Ligand-based inhibition methods involve the use of small molecules or ligands that specifically bind to CDK2, which is a crucial regulator of the cell cycle. The ligands bind to the active site of CDK2, thereby blocking its activity. These inhibitors can either mimic the structure of ATP, competing for the active site and preventing protein phosphorylation needed for cell cycle progression, or bind to allosteric sites, altering the structure of CDK2 to decrease its efficiency. [14]

Graphical abstract of CDK2 CDK2-Selective inhibitor.png
Graphical abstract of CDK2

CDK Subunits (CKS)

CDKs are essential for the control and regulation of the cell cycle. They are associated with small regulatory subunits regulatory subunits (CKSs). In mammalian cells, two CKSs are known: CKS1 and CKS2. These proteins are necessary for the proper functioning of CDKs, although their exact functions are not yet fully known. An interaction occurs between CKS1 and the carboxy-terminal lobe of CDKs, where they bind together. This binding increases the affinity of the cyclin-CDK complex for its substrates, especially those with multiple phosphorylation sites, thus contributing the promotion of cell proliferation. [20]

Non-Cyclin Activators

Viral Cyclins

Viruses can encode proteins with sequence homology to cyclins. One much-studied example is K-cyclin (or v-cyclin) from Kaposi sarcoma herpes virus (see Kaposi's sarcoma), which activates CDK6. The vCyclin-CDK6 complex promotes an accelerated transition from G1 to S phase in the cell by phosphorylating pRb and releasing E2F. This leads to the removal of inhibition on Cyclin E–CDK2's enzymatic activity. It is shown that vCyclin contributes to promoting transformation and tumorigenesis, mainly through its effect on p27 pSer10 phosphorylation and cytoplasmic sequestration. [21]

CDK5 Activators

Two protein types, p35 and p39, responsible for increasing the activity of CDK5 during neuronal differentiation in postnatal development. [22] p35 and p39 play a crucial role in a unique mechanism for regulating CDK5 activity in neuronal development and network formation. The activation of CDK with these cofactors (p35 and p39) does not require phosphorylation of the activation loop, which is different from the traditional activation of many other kinases. This highlights the importance of activating CDK5 activity, which is critical for proper neuronal development, dendritic spine and synapse formation, as well as in response to epileptic events. [22] [23]

RINGO/Speedy

Proteins in the RINGO/Speedy group represent a standout bunch among proteins that don't share amino acid sequence homology with the cyclin family. They play a crucial role in activating CDKs. Originally identified in Xenopus, these proteins primarily bind to and activate CDK1 and CDK2, despite lacking homology to cyclins. What is particularly interesting, is that CDKs activated by RINGO/Speedy can phosphorylate different sites than those targeted by cyclin-activated CDKs, indicating a unique mode of action for these non-cyclin CDK activators. [24]

Medical Significance

CDKs and Cancer

The dysregulation of CDKs and cyclins disrupts the cell cycle coordination, which makes them involved in the pathogenesis of several diseases, mainly cancers. Thus, studies of cyclins and cyclin-dependent kinases (CDK) are essential for advancing the understanding of cancer characteristics. [2] [25] Research has shown that alterations in cyclins, CDKs, and CDK inhibitors (CKIs) are common in most cancers, involving chromosomal translocations, point mutations, insertions, deletions, gene overexpression, frame-shift mutations, missense mutations, or splicing errors. [2]

The dysregulation of the CDK4/6-RB pathway is a common feature in many cancers, often resulting from various mechanisms that inactivate the cyclin D-CDK4/6 complex. Several signals can lead to overexpression of cyclin D and enhance CDK4/6 activity, contributing toward tumorigenesis. [1] [2] Additionally, the CDK4/6-RB pathway interacts with the p53 signaling pathway via p21CIP1 transcription, which can inhibit both cyclin D-CDK4/6 and cyclin E-CDK2 complexes. Mutations in p53 can deactivate the G1 checkpoint, further promoting uncontrolled proliferation. [1] [2]

CDK Inhibitors and Therapeutic Potential

Due to their central role in regulating cell cycle progression and cell proliferation, CDKs are considered ideal therapeutic targets for cancer. [25] The following CDK4/6 inhibitors mark a significant advancement in cancer treatment, offering targeted therapies that are effective and have a manageable side effect profile.

  1. Palbociclib, one of the first CDK4/6 inhibitors approved by the FDA, has become essential in the treatment of HR+/HER2- advanced or metastatic breast cancer, often in combination with endocrine therapy. [26]
  2. Ribociclib, demonstrating similar efficacy to palbociclib, is also approved for HR+/HER2- advanced breast cancer and offers benefits for a younger patient demographic. [27]
  3. Abemaciclib stands out by being usable as monotherapy, in addition to combination treatment, for certain HR+/HER2- breast cancer patients. It has also shown effectiveness in treating patients with brain metastases. [27]
  4. Trilaciclib has proven its value by improving patients' quality of life during cancer treatment by reducing the risk of chemotherapy-induced myelosuppression, a common side effect that can lead to treatment delays and dose reductions. [27]
Table 3: Cyclin-dependent kinase inhibitor drugs [28] [29]
DrugCDKs InhibitedCondition or disease
Flavopiridol (alvocidib)1, 2, 4, 6, 9Acute Myeloid Leukemia (AML)
Roscovitine (Seliciclib)2, 7, 9Pituitary Cushing Disease

Cystic Fibrosis, Advanced Solid Tumors

Lung Cancer

Dinaclib1, 2, 5, 9Chronic Lymphocytic Leukemia (CLL)

Breast and Lung Cancers

Milciclib1, 2, 4, 7Hepatocellular Carcinoma (HCC)

Thymic Carcinoma

Palbociclib4, 6Breast Cancer

Head and Neck, Brain, Colon, and other Solid Cancers

Ribociclib4, 6HR+/HER2- Breast Cancer

Prostate, and other Solid Cancers

Abemaciclib4, 6HR+/HER2- Breast Cancer

Lung, Brain, Colon, and other Solid Cancers

Meriolin1, 2, 5, 9Neuroblastoma, Glioma, Myeloma, Colon Cancer
Variolin B1, 2, 5, 9Murine Leukemia
Roniciclib1, 2, 4, 7, 9Lung and Advanced Solid Cancers
Meridianin E1, 5, 9Larynx Carcinoma

Myeloid Leukemia

Nortopsentins1Malignant Pleural Mesothelioma (MPM)

Challenges and Future Potensial

Complications of developing a CDK drug include the fact that many CDKs are not involved in the cell cycle, but other processes such as transcription, neural physiology, and glucose homeostasis. [30] More research is required, however, because disruption of the CDK-mediated pathway has potentially serious consequences; while CDK inhibitors seem promising, it has to be determined how side-effects can be limited so that only target cells are affected. As such diseases are currently treated with glucocorticoids. [31] The comparison with glucocorticoids serves to illustrate the potential benefits of CDK inhibitors, assuming their side effects can be more narrowly targeted or minimized. [32]

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-dependent kinase complex</span>

A cyclin-dependent kinase complex 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. 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.

<span class="mw-page-title-main">Restriction point</span> Animal cell cycle checkpoint

The restriction point (R), also known as the Start or G1/S checkpoint, is a cell cycle checkpoint in the G1 phase of the animal cell cycle at which the cell becomes "committed" to the cell cycle, and after which extracellular signals are no longer required to stimulate proliferation. The defining biochemical feature of the restriction point is the activation of G1/S- and S-phase cyclin-CDK complexes, which in turn phosphorylate proteins that initiate DNA replication, centrosome duplication, and other early cell cycle events. It is one of three main cell cycle checkpoints, the other two being the G2-M DNA damage checkpoint and the spindle checkpoint.

<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.

INK4 is a family of cyclin-dependent kinase inhibitors (CKIs). The members of this family (p16INK4a, p15INK4b, p18INK4c, p19INK4d) are inhibitors of CDK4 (hence their name INhibitors of CDK4), and of CDK6. The other family of CKIs, CIP/KIP proteins are capable of inhibiting all CDKs. Enforced expression of INK4 proteins can lead to G1 arrest by promoting redistribution of Cip/Kip proteins and blocking cyclin E-CDK2 activity. In cycling cells, there is a resassortment of Cip/Kip proteins between CDK4/5 and CDK2 as cells progress through G1. Their function, inhibiting CDK4/6, is to block progression of the cell cycle beyond the G1 restriction point. In addition, INK4 proteins play roles in cellular senescence, apoptosis and DNA repair.

<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 4</span> Human protein

Cyclin-dependent kinase 4 also known as cell division protein kinase 4 is an enzyme that in humans is encoded by the CDK4 gene. CDK4 is a member of the cyclin-dependent kinase family.

<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.

The Cyclin D/Cdk4 complex is a multi-protein structure consisting of the proteins Cyclin D and cyclin-dependent kinase 4, or Cdk4, a serine-threonine kinase. This complex is one of many cyclin/cyclin-dependent kinase complexes that are the "hearts of the cell-cycle control system" and govern the cell cycle and its progression. As its name would suggest, the cyclin-dependent kinase is only active and able to phosphorylate its substrates when it is bound by the corresponding cyclin. The Cyclin D/Cdk4 complex is integral for the progression of the cell from the Growth 1 phase to the Synthesis phase of the cell cycle, for the Start or G1/S checkpoint.

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.

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.

The CIP/KIP family is one of two families of mammalian cyclin dependent kinase (CDK) inhibitors (CKIs) involved in regulating the cell cycle. The CIP/KIP family is made up of three proteins: p21cip1/waf1, P27kip1, p57kip2 These proteins share sequence homology at the N-terminal domain which allows them to bind to both the cyclin and CDK. Their activity primarily involves the binding and inhibition of G1/S- and S-Cdks; however, they have also been shown to play an important role in activating the G1-CDKs CDK4 and CDK6. In addition, more recent work has shown that CIP/KIP family members have a number of CDK-independent roles involving regulation of transcription, apoptosis, and the cytoskeleton.

The Neuronal cell cycle represents the life cycle of the biological cell, its creation, reproduction and eventual death. The process by which cells divide into two daughter cells is called mitosis. Once these cells are formed they enter G1, the phase in which many of the proteins needed to replicate DNA are made. After G1, the cells enter S phase during which the DNA is replicated. After S, the cell will enter G2 where the proteins required for mitosis to occur are synthesized. Unlike most cell types however, neurons are generally considered incapable of proliferating once they are differentiated, as they are in the adult nervous system. Nevertheless, it remains plausible that neurons may re-enter the cell cycle under certain circumstances. Sympathetic and cortical neurons, for example, try to reactivate the cell cycle when subjected to acute insults such as DNA damage, oxidative stress, and excitotoxicity. This process is referred to as “abortive cell cycle re-entry” because the cells usually die in the G1/S checkpoint before DNA has been replicated.

<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

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