INK4

Last updated

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. [1] Their function, inhibiting CDK4/6, is to block progression of the cell cycle beyond the G1 restriction point. [2] In addition, INK4 proteins play roles in cellular senescence, apoptosis and DNA repair. [3]

Contents

INK4 proteins are tumor suppressors and loss-of-function mutations lead to carcinogenesis. [4]

INK4 proteins are highly similar in terms of structure and function, with up to 85% amino acid similarity. [1] They contain multiple ankyrin repeats. [3]

Genes

The INK4a/ARF/INK4b Locus. Regulation of INK4 and ARF.png
The INK4a/ARF/INK4b Locus.

The INK4a/ARF/INK4b locus encodes three genes (p15INK4b, ARF, and p16INK4a) in a 35-kilobase stretch of the human genome. P15INK4b has a different reading frame that is physically separated from p16INK4a and ARF. P16INK4a and ARF have different first exons that are spliced to the same second and third exon. While those second and third exons are shared by p16INK4a and ARF, the proteins are encoded in different reading frames meaning that p16INK4a and ARF are not isoforms, nor do they share any amino acid homology. [1]

Evolution

Polymorphisms of the p15INK4b/p16INK4a homolog were found to segregate with melanoma susceptibility in Xiphophorus indicating that INK4 proteins have been involved with tumor suppression for over 350 million years. Furthermore, the older INK4-based system has been further bolstered by the evolution of the recent addition of the ARF-based anti-cancer response. [1]

Function

INK4 in cyclin/CDK pathway INK4 pathway.jpg
INK4 in cyclin/CDK pathway

INK4 proteins are cell-cycle inhibitors. When they bind to CDK4 and CDK6, they induce an allosteric change that leads to the formation of CDK-INK4 complexes rather than CDK-cyclin complexes. This leads to an inhibition of retinoblastoma (Rb) phosphorylation downstream. Therefore, the expression of p15INK4b or p16INK4A keeps the Rb-family proteins hypophosphorylated. This allows the hypophosphorylated Rb to repress transcription of S-phase genes causing cell cycle arrest in the G1 phase. [5]

Subsets

P16INK4a

P16 is formed from four ankyrin repeat (AR) motifs that exhibit a helix-turn-helix conformation except that the first helix in the second AR consists of four residues. [6] P16 regulation involves epigenetic control and multiple transcription factors. PRC1, PRC2, YY1, and Id1 play a role in the suppression of p16INK4A expression and transcription factors CTCF, Sp1, and ETs activate p16INK4A transcription. [7] In knockout experiments, it was found that mice lacking just p16INK4a were more prone to spontaneous cancers. Mice lacking both p16INK4a and ARF were found to be even more tumor prone than the mice lacking just p16INK4a. [1]

P15INK4b

P15 is also formed from four ankyrin repeat (AR) motifs. Expression of P15INK4b is induced by TGF-b indicating its role as a potential downstream effector of TGF-b mediated growth arrest. [8]

P18INK4c

P18INK4c has been shown to play an important role in modulating TCR-mediated T cell proliferation. The loss of p18INK4c in T cells reduced the requirement of CD28 costimulation for efficient T cell proliferation. Other INK4 family members did not affect this process. Furthermore, it was shown that p18INK4c is preferentially inhibitory to CDK6, but not CDK4 activity in activated T cells that suggest p18INK4c may set an inhibitory threshold in resting T cells. [9]

Clinical significance

Role in cancer

Cells containing oncogenic mutations in-vivo often responded by activating the INK4A/ARF/INK4B locus that encodes the INK4 tumor suppressor proteins. The unusual genomic arrangement of the INK4a/ARF/INK4b locus functions as a weakness in our anti-cancer defenses. This is due to the fact that three crucial regulators of the RB and p53 (regulated by ARF) are vulnerable to one single, small deletion. This observation yields two possible opposing conclusions: Either tumor formation does not provide any evolutionary selection pressure because the overlapping INK4a/ARF/INK4b is not selected against or tumorigenesis provides such a strong pressure, that an entire group of genes has been selected for at the INK4a/ARF/INK4b locus to prevent cancer. The response of the INK4a/ARF/INK4b locus efficiently prevents cancers that could occur to the constant oncogenic mutations that occur in long-lived mammals.

When the INK4a/ARF/INK4b locus was overexpressed, the mice demonstrated a 3-fold reduction in the incidence of spontaneous cancers. This evidence further indicated that the INK4a/ARF/INK4b locus in mice plays a role in tumor suppression. [1]

Role in aging

The INK4 family has been implicated in the aging process. The expression of p16INK4a increases with aging in many tissues of rodents and humans. [1] It was also shown that INK4a/ARF deficient animals increase an age-related decline in T-cell responsiveness to CD3 and CD28, which is a hallmark of aging. Furthermore, neural stem cells from Bmi-1- deficient animals demonstrate increased INK4a/ARF expression and impaired regenerative potential. The phenotype; however, can be rescued by p16INK4a deficiency implying that while p16INK4a can potentially be used as a biomarker of physiologic, rather than chronologic age, it is also an effector of aging. The mechanism by which it does this is by limiting the self-renewal capacity of disparate tissues such as lymphoid organs, bone marrow, and the brain. [10]

Regulation of INK4 expression

Initially, it was thought that each INK4 family member was structurally redundant and equally potent. It was later found; however, that INK4 family members are differentially expressed during mouse development. The diversity in expression pattern indicates that the INK4 gene family may have cell lineage-specific or tissue-specific functions. [11] Evidence has shown that INK4a/ARF expression increase at an early stage of tumorigenesis, but the precise stimuli relevant to cancer that induces the expression of the locus is unknown. Expression of p15INK4b does not correlate with p16INK4a in many normal rodent tissues. Induction and repression of p15INK4b; however, has been noted in response to a few signaling events such as RAS activation, that also induce INK4/ARF expression. RAS activation might lead to increased INK4/ARF expression potentially through ERK-mediated activation of Ets1/2 to induce p16INK4. A few repressors of INK4a/ARF/INK4b expression have been identified as well. T box proteins and the polycomb group have been shown to repress p16INK4a, p15INK4b, and ARF. [1]

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">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.

p14ARF is an alternate reading frame protein product of the CDKN2A locus. p14ARF is induced in response to elevated mitogenic stimulation, such as aberrant growth signaling from MYC and Ras (protein). It accumulates mainly in the nucleolus where it forms stable complexes with NPM or Mdm2. These interactions allow p14ARF to act as a tumor suppressor by inhibiting ribosome biogenesis or initiating p53-dependent cell cycle arrest and apoptosis, respectively. p14ARF is an atypical protein, in terms of its transcription, its amino acid composition, and its degradation: it is transcribed in an alternate reading frame of a different protein, it is highly basic, and it is polyubiquinated at the N-terminus.

p16 Mammalian protein found in Homo sapiens

p16, is a protein that slows cell division by slowing the progression of the cell cycle from the G1 phase to the S phase, thereby acting as a tumor suppressor. It is encoded by the CDKN2A gene. A deletion in this gene can result in insufficient or non-functional p16, accelerating the cell cycle and resulting in many types of cancer.

<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 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-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 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 D2</span> Protein-coding gene in humans

G1/S-specific cyclin-D2 is a protein that in humans is encoded by the CCND2 gene.

<span class="mw-page-title-main">CDKN2B</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 4 inhibitor B also known as multiple tumor suppressor 2 (MTS-2) or p15INK4b is a protein that is encoded by the CDKN2B gene in humans.

<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.

<span class="mw-page-title-main">CDKN2D</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 4 inhibitor D is an enzyme that in humans is encoded by the CDKN2D gene.

<span class="mw-page-title-main">CDKN2A</span> Protein-coding gene in the species Homo sapiens

CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. It is ubiquitously expressed in many tissues and cell types. The gene codes for two proteins, including the INK4 family member p16 and p14arf. Both act as tumor suppressors by regulating the cell cycle. p16 inhibits cyclin dependent kinases 4 and 6 and thereby activates the retinoblastoma (Rb) family of proteins, which block traversal from G1 to S-phase. p14ARF activates the p53 tumor suppressor. Somatic mutations of CDKN2A are common in the majority of human cancers, with estimates that CDKN2A is the second most commonly inactivated gene in cancer after p53. Germline mutations of CDKN2A are associated with familial melanoma, glioblastoma and pancreatic cancer. The CDKN2A gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">Cellular senescence</span> Phenomenon characterized by the cessation of cell division

Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of approximately 50 cell population doublings before becoming senescent. This process is known as "replicative senescence", or the Hayflick limit. Hayflick's discovery of mortal cells paved the path for the discovery and understanding of cellular aging molecular pathways. Cellular senescence can be initiated by a wide variety of stress inducing factors. These stress factors include both environmental and internal damaging events, abnormal cellular growth, oxidative stress, autophagy factors, among many other things.

<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

  1. 1 2 3 4 5 6 7 8 9 10 Kim WY, Sharpless NE (October 2006). "The regulation of INK4/ARF in cancer and aging". Cell. 127 (2): 265–75. doi: 10.1016/j.cell.2006.10.003 . PMID   17055429. S2CID   18280031.
  2. ↑ Ortega S, Malumbres M, Barbacid M (March 2002). "Cyclin D-dependent kinases, INK4 inhibitors and cancer". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1602 (1): 73–87. doi:10.1016/S0304-419X(02)00037-9. PMID   11960696.
  3. 1 2 Cánepa ET, Scassa ME, Ceruti JM, Marazita MC, Carcagno AL, Sirkin PF, Ogara MF (July 2007). "INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions". IUBMB Life. 59 (7): 419–26. doi: 10.1080/15216540701488358 . hdl: 11336/30965 . PMID   17654117. S2CID   9339088.
  4. ↑ Roussel MF (September 1999). "The INK4 family of cell cycle inhibitors in cancer". Oncogene. 18 (38): 5311–7. doi: 10.1038/sj.onc.1202998 . PMID   10498883.
  5. ↑ Sherr CJ (July 2000). "The Pezcoller lecture: cancer cell cycles revisited". Cancer Research. 60 (14): 3689–95. PMID   10919634.
  6. ↑ Li J, Poi MJ, Tsai MD (June 2011). "Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer". Biochemistry. 50 (25): 5566–82. doi:10.1021/bi200642e. PMC   3127263 . PMID   21619050.
  7. ↑ Rayess H, Wang MB, Srivatsan ES (April 2012). "Cellular senescence and tumor suppressor gene p16". International Journal of Cancer. 130 (8): 1715–25. doi:10.1002/ijc.27316. PMC   3288293 . PMID   22025288.
  8. ↑ Fares J, Wolff L, Bies J (January 2011). Huret JL, Ohgami RS, Dal Cin P, Rivas JM, Dessen P (eds.). "CDKN2B (cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4))". Atlas of genetics and cytogenetics in oncology and haematology. Retrieved 2018-12-16.
  9. ↑ Kovalev GI, Franklin DS, Coffield VM, Xiong Y, Su L (September 2001). "An important role of CDK inhibitor p18(INK4c) in modulating antigen receptor-mediated T cell proliferation". Journal of Immunology. 167 (6): 3285–92. doi:10.4049/jimmunol.167.6.3285. PMC   4435948 . PMID   11544316.
  10. ↑ Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE (November 2004). "Ink4a/Arf expression is a biomarker of aging". The Journal of Clinical Investigation. 114 (9): 1299–307. doi:10.1172/JCI22475. PMC   524230 . PMID   15520862.
  11. ↑ Cánepa ET, Scassa ME, Ceruti JM, Marazita MC, Carcagno AL, Sirkin PF, Ogara MF (July 2007). "INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions". IUBMB Life. 59 (7): 419–26. doi: 10.1080/15216540701488358 . hdl: 11336/30965 . PMID   17654117. S2CID   9339088.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.