Cyclin D/Cdk4

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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" [1] 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.

Contents

Basic Mechanism

Role of CDK4, cyklin D, Rb and E2F in cell cycle regulation. Role of CDK4, cyklin D, Rb and E2F in cell cycle regulation.jpg
Role of CDK4, cyklin D, Rb and E2F in cell cycle regulation.

Under non-dividing conditions (when the cell is in the G0 phase of the cell cycle), Retinoblastoma protein (Rb) is bound with the E2F transcription factor. During the G0 to G1 transition, growth factor stimulates the synthesis of Cyclin D protein, [2] whose concentration increases until it peaks around the G1/S transition.

In the early to middle stages of G1 phase, Cyclin D binds to the constitutively expressed Cdk4 protein, [3] which creates an activated CyclinD/Cdk4 complex. Once activated, the Cyclin D/Cdk4 complex docks at a C-terminus helix on the Retinoblastoma protein (pRb), which is driven by a recognition site for the C-terminus helix on Cyclin D. [4] Upon docking, CyclinD/Cdk4 mono-phosphorylates the Rb protein, [5] which disrupts the Rb/E2F interaction and is sufficient to initiate E2F induction. [6] E2F transcriptionally activates a number of downstream target genes required in the next stages of the cell cycle and in DNA replication by binding to their DNA promoter regions. These genes include the cyclin E and A genes, and other genes associated with the G1/S transition.

Synthesis of cyclin E and subsequent binding to constitutively expressed Cdk2 leads to a surge in activity of the cyclin E/Cdk2 complex, [7] which is responsible for hyperphosphorylation of Rb. [5] Rb hyperphosphorylation leads to the complete inactivation of Rb and release of E2F, initiating a positive feedback loop between E2F and cyclin E/Cdk2 that stimulates expression of E2F-driven G1/S transition genes, and, at a certain level, activates the bistable switch that drives irreversible progression into S phase. [6] [7]

Regulation

There are multiple regulation points within this signaling pathway. First and foremost, under non-dividing conditions multiple proteins can inhibit the Cyclin D/Cdk4 complex by binding Cdk4 and inhibiting its association with Cyclin D. Primarily, this is accomplished by p27 but it can also be done by p16 and p21. However, this pathway is stimulated by the upstream binding of growth factors (GF), either from within the cell itself or from neighboring cells. Stimulation by growth factors activates any of a number of receptor tyrosine kinase (RTK) proteins. These receptor tyrosine kinases in turn phosphorylate and activate many other proteins, including Fos/Jun/Myc and phosphatidylinositol 3 kinase (PI-3-K). Fos/Jun/Myc helps to activate the Cyclin D/Cdk4 complex. Phosphatidylinositol 3 kinase phosphorylates p27 (or p16 or p21) and SCF/Skp1. The phosphorylation of p27 inhibits p27's ability to bind Cdk4, thus freeing Cdk4 to associate with Cyclin D and form an active complex. SCF/Skp1 (an E3 ubiquitin ligase) helps to further inhibit p27 and thus further help activate the Cyclin D/Cdk4 complex. Also, p27 acts as an inhibitor of Cyclin E and Cyclin A. So, its inhibition also facilitates the activation of downstream mitotic processes, as noted above.

There are also other peripheral regulators of the Cyclin D/Cdk4 complex. In megakaryocytes, it is regulated by the GATA-1 transcription factor. [8] GATA-1 serves as an activating transcription factor of Cyclin D and potentially also as a repressor of the Cyclin D inhibitor, p16. Cdk4 also requires activation upon complex assembly with Cyclin D. This is accomplished by a Cdk activating kinase (CAK), which phosphorylates Cdk4 at threonine 172. [9]

Cancer

Disruptions in The CyclinD/Cdk4 Axis in Cancer

The function of the Cyclin D/Cdk4 complex suggests an obvious link to cancer and tumorigenesis. In fact, disruptions in the Cyclin D/Cdk4 axis that lead to increased Cyclin D/Cdk4 activity have been detected in many cancers. There are a number of drivers of these disruptions.

Disruption of the Cyclin D/Cdk4 axis through any of these three mechanisms induces phosphorylation of Rb, transcription of E2F-driven genes, uncontrolled progression through the G1/S checkpoint, and ultimately cancer cell growth. [17]


Selective Cdk4/6 Inhibitors

Given the role of Cyclin D/Cdk4 in cancer progression, the development of selective Cdk4/6 inhibitors has been of increased interest in recent years. Currently, three Cdk4/6 inhibitors have been approved or are in late-stage development: palbociclib, ribociclib, and abemaciclib. All three of these inhibitors are ATP-competitive, orally administered medications. [17]

Thus far, selective Cdk4/6 inhibitors have shown the most promise when used in combination with other anti-estrogen therapies for the treatment of hormone-receptor-positive (HR+) advanced breast cancer. In HR+ breast cancer, cells retain wildtype Rb expression and have overexpressed Cyclin D1.

Additional studies into the efficacy of these combination therapies on advanced breast cancer survival in different settings are ongoing. Based on the encouraging results from the clinical trials, additional studies are also underway to investigate the effect of the three selective Cdk4/6 inhibitors on other neoplasms like non-small cell lung cancer. [17] [21] Of note, some patients in pre-clinical and clinical settings have not responded to the Cdk4/6 inhibitors or have become resistant to them. Research into the mechanisms behind these clinical outcomes is still in progress.

Non-Canonical Roles of CyclinD/Cdk4

In addition to its canonical role in promoting progression through the cell cycle, CyclinD/Cdk4 also plays a role in regulating cell differentiation and metabolism in a variety of contexts.

Cell Differentiation

Rb can promote cell cycle differentiation by interacting with multiple different cell-type-specific transcription factors. These transcription factors include MyoD and MEF2, which regulate muscle cell differentiation, and RUNX2, which regulates osteoblast differentiation. [22] When CyclinD/Cdk4 phosphorylates and inactivates Rb, Rb’s role in driving cell differentiation via interaction with these transcription factors is inhibited. Cyclin D/Cdk4 activity can also directly block the association of MEF2 with GRIP-1, a transcription co-activator, which inhibits MEF2’s ability to induce muscle gene expression and subsequent differentiation. [22] [23]

Cyclin D/Cdk4 activity can also regulate cell differentiation through Rb-independent pathways. For instance, CyclinD/Cdk4 activity has been shown to phosphorylate the transcription factor GATA4, which targets it for degradation and inhibits differentiation of cardiomyocytes. [24] Additionally, Cyclin D/Cdk4 activity is thought to block neurogenesis in neural stem cells and promote the expansion of basal progenitors. [25]

Metabolism

Gluconeogenesis in the liver is critical for survival during times of fasting and starvation. CyclinD1/Cdk4 activity has been shown to play a role in regulating glucose homeostasis by suppressing hepatic gluconeogenesis via phosphorylation-induced inhibition of the peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α). (PGC1α) is a transcriptional coactivator that drives the gene expression programming for gluconeogenesis in the liver. [26] Additional research has shown that the CyclinD/Cdk4/Rb/ER2F pathway also influences the expression of Kir6.2, a subunit of the ATP-sensitive K channel that regulates glucose-induced insulin secretion. When the CyclinD/Cdk4 complex is inhibited, Kir6.2 expression is downregulated, and there is impaired insulin secretion and glucose intolerance when tested in mouse models. [27] Given that glucose homeostasis is dysregulated in diabetes, there is ongoing interest in whether the CyclinD/Cdk4 complex could be a potential target for disease treatment.

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.

G<sub>0</sub> phase Quiescent stage of the cell cycle in which the cell does not divide

The G0 phase describes a cellular state outside of the replicative cell cycle. Classically, cells were thought to enter G0 primarily due to environmental factors, like nutrient deprivation, that limited the resources necessary for proliferation. Thus it was thought of as a resting phase. G0 is now known to take different forms and occur for multiple reasons. For example, most adult neuronal cells, among the most metabolically active cells in the body, are fully differentiated and reside in a terminal G0 phase. Neurons reside in this state, not because of stochastic or limited nutrient supply, but as a part of their developmental program.

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

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. They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved. 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. 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. Deregulation of the CDK activity is linked to various pathologies, including cancer, neurodegenerative diseases, and stroke.

<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.

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.

<span class="mw-page-title-main">G1/S transition</span> Stage in cell cycle

The G1/S transition is a stage in the cell cycle at the boundary between the G1 phase, in which the cell grows, and the S phase, during which DNA is replicated. It is governed by cell cycle checkpoints to ensure cell cycle integrity and the subsequent S phase can pause in response to improperly or partially replicated DNA. During this transition the cell makes decisions to become quiescent, differentiate, make DNA repairs, or proliferate based on environmental cues and molecular signaling inputs. The G1/S transition occurs late in G1 and the absence or improper application of this highly regulated checkpoint can lead to cellular transformation and disease states such as cancer.

The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.

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">Cyclin E</span> Member of the cyclin family

Cyclin E is a member of the cyclin family.

<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.

<span class="mw-page-title-main">Cyclin D1</span> Protein found in humans

Cyclin D1 is a protein that in humans is encoded by the CCND1 gene.

<span class="mw-page-title-main">CDKN1B</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase inhibitor 1B (p27Kip1) is an enzyme inhibitor that in humans is encoded by the CDKN1B gene. It encodes a protein which belongs to the Cip/Kip family of cyclin dependent kinase (Cdk) inhibitor proteins. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. It is often referred to as a cell cycle inhibitor protein because its major function is to stop or slow down the cell division cycle.

<span class="mw-page-title-main">Cyclin A2</span> Protein-coding gene in the species Homo sapiens

Cyclin-A2 is a protein that in humans is encoded by the CCNA2 gene. It is one of the two types of cyclin A: cyclin A1 is expressed during meiosis and embryogenesis while cyclin A2 is expressed in the mitotic division of somatic cells.

<span class="mw-page-title-main">Retinoblastoma protein</span> Mammalian protein found in Homo sapiens

The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. When the cell is ready to divide, pRb is phosphorylated, inactivating it, and the cell cycle is allowed to progress. It is also a recruiter of several chromatin remodeling enzymes such as methylases and acetylases.

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.

<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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  2. ↑ Sherr, C J; Roberts, J M (1995-05-15). "Inhibitors of mammalian G1 cyclin-dependent kinases". Genes & Development. 9 (10): 1149–1163. doi:10.1101/gad.9.10.1149. ISSN   0890-9369. PMID   7758941.
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  18. ↑ Hortobagyi, Gabriel N.; Stemmer, Salomon M.; Burris, Howard A.; Yap, Yoon-Sim; et al. (2022-03-10). "Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer" (PDF). The New England Journal of Medicine. 386 (10): 942–950. doi:10.1056/NEJMoa2114663. ISSN   1533-4406. PMID   35263519.
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  26. ↑ Bhalla, Kavita; Liu, Wan-Ju; Thompson, Keyata; Anders, Lars; et al. (2014-10-01). "Cyclin D1 Represses Gluconeogenesis via Inhibition of the Transcriptional Coactivator PGC1α". Diabetes. 63 (10): 3266–3278. doi:10.2337/db13-1283. ISSN   0012-1797. PMC   4392904 . PMID   24947365.
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