CIP/KIP

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The CIP/KIP (CDK interacting protein/Kinase inhibitory protein) family is one of two families (CIP/KIP and INK4) of mammalian cyclin dependent kinase (CDK) inhibitors (CKIs) involved in regulating the cell cycle. [1] [2] The CIP/KIP family is made up of three proteins: p21cip1/waf1, [3] [4] P27kip1, [5] p57kip2 [6] [7] 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. [8] [9] 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. [10] [11] [12] [13]

Contents

Role in cell cycle progression

CIP/KIP family proteins bind a wide range of G1/S and S-phase cyclin-CDK complexes including cyclin D-CDK4,6 and cyclin E-, A-CDK2 complexes. Traditionally it was assumed that CIP/KIP proteins played a role in inhibiting all of these complexes; however it was later discovered that CIP/KIP proteins, while inhibiting CDK2 activity, may also activate cyclin D-CDK4,6 activity by facilitating stable binding between cyclin D and CDK4,6.

cyclinA-CDK2 regulation

The crystal structure of p27 in a complex with cyclinA-CDK2 was published in 1996. [14] The structure shows that p27 interacts with both cyclin A and CDK2. In addition, p27 mimics ATP and inserts itself into the ATP binding site thus preventing ATP binding. This mechanism blocks any kinase activity and prevents downstream hyper-phosphorylation of Rb that allows release of the E2F transcription factor and transcription of cell cycle-related genes.

cyclinD-CDK4,6 regulation

Cyclin D has low affinity for its CDK. Therefore, it was hypothesized that additional proteins were needed to allow for a stable cyclin D-CDK4,6 complex. Growing evidence has shown that CIP/KIP proteins are involved in this stabilization. The first evidence of this came from the observation that p27 would frequently immunoprecipitate with active cyclin D-CDK4 complexes. Futhurmore, mouse embryonic fibroblasts deficient for p21 and p27 had lower levels of cyclin D1 and immunoprecipitated cyclinD-CDK complexes had no kinase activity. [8] [9] These effects were rescued with reintroduction of p21 and p27, but not reintroduction of cyclin D1 suggesting that CIP/KIP proteins are crucial for cyclin D-CDK activity. [15] In vitro evidence has shown that cyclin D-CDK binding of CIP/KIP is not restricted to p21 and p27 and can also be performed by p57. [9]

Model of CIP/KIP G1-S regulation

The divergent role of CIP/KIP proteins based on whether they are bound to CDK2 or CDK4,6 has led to a model whereby CIP/KIP proteins bind to and inactivate CDK2 complexes in early G1; however, following production of Cyclin D, CIP/KIP proteins are removed and repurposed towards cyclin D-CDK stabilization. This sequestering then frees up Cyclin A-, E-CDK2 to hyperphosphorylate Rb and promote progression of the cell cycle. This model is supported by the finding that expression of either wild-type or catalytically inactive CDK4 can sequester CIP/KIP proteins resulting in cyclin E-CDK2 activation. This finding suggests that the ability of cyclinD-CDK complexes to sequester CIP/KIP proteins is predominates their inhibitory activity of CDK2. [1] [2] [16]

Roles outside of cell cycle progression

Apoptosis

CIP/KIP proteins have been shown to regulate apoptosis via a variety of mechanisms. p21 and p27 cleavage are known to promote apoptosis through activation of CDK2 activation. [17] p57 has also been shown to inhibit apoptosis as p57 null mice show a range of developmental defects including cleft palate and a range of intestinal abnormalities associated with increased apoptosis. [18]

CIP/KIP proteins have also been shown to regulate apoptosis via CDK-independent mechanisms. p57 can bind JNK1/SAPK, a stress-related kinase, and block its activity, protecting against JNK1-regulated apoptosis. [19]

Transcription

CIP/KIP proteins can regulate transcription indirectly through stabilization of cyclinD-CDK and uninhibiting cyclin-CDK2 complexes that are crucial for Rb phosphorylation and release of the E2F transcription factor. CIP/KIP proteins have also been shown to directly bind transcription factors. For example. p27 has been shown to bind to and stabilize Neurogenin-2 promoting differentiation of neural progenitor cells. [20]

Cytoskeleton

CIP/KIP proteins have previously been shown to inhibit Rho/ROCK/LIMK/Cofilin signaling. [12] In addition, fibroblasts deficient for p27 have reduced motility. [21] p27 deficient fibroblasts also have increased levels of stress fibers and focal adhesions. [12] The role of CIP/KIP proteins in motility has also become particularly of interest in cancer where misregulation of p27 could result in increased proliferation and increased motility which may contribute to more invasive cancers.

Role in cancer and disease

As cyclin-dependent kinase inhibitors, CIP/KIP proteins have been classically viewed as tumor suppressors; however, the exact role of CIP/KIP proteins in cancer progression has been difficult to assess because a complete loss of CIP/KIP function has not been observed in any cancers. [2] However, low-expression p27 has been observed in a wide variety of tumors and is associated with increased tumor aggression. [22] [23] In addition, p27 null mice spontaneously develop tumors in the pituitary gland and are more susceptible to chemical carcinogens or irradiation. [24] [25] [26] In particular, not only the expression of p27, but also the subcellular localization of p27 is thought to play an important role in tumorigenesis. [27] Elevated cytoplasmic localization of p27 has been observed in a number of cancers and has been associated with a poor prognosis. This mislocalization could potentially explain how p27 could simultaneously promote cell cycle progression and increased motility in cancers. A similar model could also be equally true of other CIP/KIP proteins. [27] [28] [29] [30]

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</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.

<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.

p21 Protein

p21Cip1, also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated with inhibition of CDK2. p21 represents a major target of p53 activity and thus is associated with linking DNA damage to cell cycle arrest. This protein is encoded by the CDKN1A gene located on chromosome 6 (6p21.2) in humans.

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

Cyclin E is a member of the cyclin family.

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.

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<span class="mw-page-title-main">P27 cis-regulatory element</span>

The p27 cis-regulatory element is a structured G/C rich RNA element which is involved in controlling cell cycle regulated translation of the p27kip protein in human cells.

<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">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">SKP2</span> Protein-coding gene in the species Homo sapiens

S-phase kinase-associated protein 2 is an enzyme that in humans is encoded by the SKP2 gene.

<span class="mw-page-title-main">Cyclin E1</span> Protein-coding gene in the species Homo sapiens

G1/S-specific cyclin-E1 is a protein that in humans is encoded by the CCNE1 gene.

<span class="mw-page-title-main">Cyclin-dependent kinase inhibitor 1C</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase inhibitor 1C , also known as CDKN1C, is a protein which in humans is encoded by the CDKN1C imprinted gene.

<span class="mw-page-title-main">CDKN2C</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 4 inhibitor C is an enzyme that in humans is encoded by the CDKN2C gene.

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.

References

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