Cyclin-dependent kinase 2

Last updated
CDK2
Protein CDK2 PDB 1aq1.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CDK2 , cyclin-dependent kinase 2, A630093N05Rik, CDKN2, p33(CDK2), cyclin dependent kinase 2
External IDs OMIM: 116953; MGI: 104772; HomoloGene: 74409; GeneCards: CDK2; OMA:CDK2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1017

12566

Ensembl

ENSG00000123374

ENSMUSG00000025358

UniProt

P24941

P97377

RefSeq (mRNA)

NM_001290230
NM_001798
NM_052827

NM_016756
NM_183417

RefSeq (protein)

NP_001277159
NP_001789
NP_439892

NP_058036
NP_904326

Location (UCSC) Chr 12: 55.97 – 55.97 Mb Chr 10: 128.53 – 128.54 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] [6] 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. [7] Its activity is also regulated by phosphorylation. Multiple alternatively spliced variants and multiple transcription initiation sites of this gene have been reported. [8] 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. [9]

Dispensability in normally functioning tissue

Original cell-culture based experiments demonstrated cell cycle arrest at the G1-S transition resulting from the deletion of Cdk2. [10] Later experiments showed that Cdk2 deletions lengthened the G1 phase of the cell cycle in mouse embryo fibroblasts. However, they still entered S phase after this period and were able to complete the remaining phases of the cell cycle. [11] When Cdk2 was deleted in mice, the animals remained viable despite a reduction in body size. However, meiotic function of both male and female mice was inhibited. This suggests that Cdk2 is non-essential for the cell cycle of healthy cells, but essential for meiosis and reproduction. [10] Cells in Cdk2 knockout mice likely undergo fewer divisions, contributing to the reduction in body size. Germ cells also stop dividing at prophase of meiosis, leading to reproductive sterility. [11] Cdk1 is now believed to compensate for many aspects of Cdk2 deletion, except for meiotic function. [10]

Mechanism of activation

Cyclin-dependent kinase 2 is structured in two lobes. The lobe beginning at the N-terminus (N-lobe) contains many beta sheets, while the C-terminus lobe (C-lobe) is rich in alpha helices. [7] Cdk2 is capable of binding to many different cyclins, including cyclins A, B, E, and possibly C. [10] Recent studies suggest Cdk2 binds preferentially to cyclins A and E, while Cdk1 prefers cyclins A and B. [12]

Cdk2 (blue) and its binding partner, cyclin A (red). CDK2CyclinA Cropped.png
Cdk2 (blue) and its binding partner, cyclin A (red).

Cdk2 becomes active when a cyclin protein (either A or E) binds at the active site located between the N and C lobes of the kinase. Due to the location of the active site, partner cyclins interact with both lobes of Cdk2. Cdk2 contains an important alpha helix located in the C lobe of the kinase, called the C-helix or the PSTAIRE-helix. Hydrophobic interactions cause the C-helix to associate with another helix in the activating cyclin. Activation induces a conformational change where the helix rotates and moves closer to the N-lobe.[ citation needed ] This allows the glutamic acid located on the C-helix to form an ion pair with a nearby lysine side chain. The significance of this movement is that it brings the side chain of Glu 51, which belongs to a triad of catalytic site residues conserved in all eukaryotic kinases, into the catalytic site. This triad (Lys 33, Glu 51 and Asp 145) is involved in ATP phosphate orientation and magnesium coordination, and is thought to be critical for catalysis. This conformational change also relocates the activation loop to the C-lobe, revealing the ATP binding site now available for new interactions. Finally, the Threonine-160 residue is exposed and phosphorylated as the C-lobe activation segment is displaced from the catalytic site and the threonine residue is no longer sterically hindered. The phosphorylated threonine residue creates stability in the final enzyme conformation. It is important to note that throughout this activation process, cyclins binding to Cdk2 do not undergo any conformational change. [14] [7]

Cdk2 (blue) and its binding partner cyclin E (orange). CDK2CyclinE Cropped.png
Cdk2 (blue) and its binding partner cyclin E (orange).

Role in DNA replication

The success of the cell division process is dependent on the precise regulation of processes at both cellular and tissue levels. Complex interactions between proteins and DNA within the cell allow genomic DNA to be passed to daughter cells. Interactions between cells and extracellular matrix proteins allow new cells to be incorporated into existing tissues. At the cellular level, the process is controlled by different levels of cyclin-dependent kinases (Cdks) and their partner cyclins. Cells utilize various checkpoints as a means of delaying cell cycle progression until it can repair defects. [16]

Cdk2 is active during G1 and S phase of the cell cycle, and therefore acts as a G1-S phase checkpoint control. Prior to G1 phase, levels of Cdk4 and Cdk6 increase along with cyclin D. This allows for the partial phosphorylation of Rb, and partial activation of E2F at the beginning of G1 phase, which promotes cyclin E synthesis and increased Cdk2 activity. At the end of G1 phase, the Cdk2/Cyclin E complex reaches maximum activity and plays a significant role in the initiation of S phase. [17] Other non-Cdk proteins also become active during the G1-S phase transition. For example, the retinoblastoma (Rb) and p27 proteins are phosphorylated by Cdk2 – cyclin A/E complexes, fully deactivating them. [18] This allows E2F transcription factors to express genes that promote entry into S phase where DNA is replicated prior to division. [19] [20] [18] Additionally, NPAT, a known substrate of the Cdk2-Cyclin E complex, functions to activate histone gene transcription when phosphorylated. [21] This increases the synthesis of histone proteins (the major protein component of chromatin), and subsequently supports the DNA replication stage of the cell cycle. Finally, at the end of S phase, the ubiquitin proteasome degrades cyclin E. [11]

Cancer cell proliferation

Although Cdk2 is mostly dispensable in the cell cycle of normally functioning cells, it is critical to the abnormal growth processes of cancer cells. The CCNE1 gene produces cyclin E, one of the two major protein binding partners of Cdk2. Overexpression of CCNE1 occurs in many tumor cells, causing the cells to become dependent on Cdk2 and cyclin E. [12] Abnormal cyclin E activity is also observed in breast, lung, colorectal, gastric, and bone cancers, as well as in leukemia and lymphoma. [17] Likewise, abnormal expression of cyclin A2 is associated with chromosomal instability and tumor proliferation, while inhibition leads to decreased tumor growth. [22] Therefore, CDK2 and its cyclin binding partners represent possible therapeutic targets for new cancer therapeutics. [12] Pre-clinical models have shown preliminary success in limiting tumor growth, and have also been observed to reduce side effects of current chemotherapy drugs. [23] [24] [25]

Identifying selective Cdk2 inhibitors is difficult due to the extreme similarity between the active sites of Cdk2 and other Cdks, especially Cdk1. [12] Cdk1 is the only essential cyclin dependent kinase in the cell cycle, and inhibition could lead to unintended side effects. [26] Most CDK2 inhibitor candidates target the ATP binding site and can be divided into two main subclasses: type I and type II. Type I inhibitors competitively target the ATP binding site in its active state. Type II inhibitors target CDK2 in its unbound state, either occupying the ATP binding site or hydrophobic pocket within the kinase. Type II inhibitors are believed to be more selective. [24] Recently, the availability of new CDK crystal structures led to the identification of a potential allosteric binding site near the C-helix. Inhibitors of this allosteric site are classified as type III inhibitors. [27] Another possible target is the T-loop of CDK2. When cyclin A binds to CDK2, the N-terminal lobe rotates to activate the ATP binding site and switch the position of the activation loop, called the T-loop. [28]

Inhibitors

Interpretation of dynamic simulations and binding free energy studies unveiled that Ligand2 (Out of 17 in-house synthesized pyrrolone-fused benzosuberene (PBS) compounds) has a stable and equivalent free energy to Flavopiridol, SU9516, and CVT-313 inhibitors. Ligand2 scrutinized as a selective inhibitor of CDK2 without off-target binding (CDK1 and CDK9) based on ligand efficiency and binding affinity. [29]

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


Known CDK inhibitors are p21Cip1 (CDKN1A) and p27Kip1 (CDKN1B). [30]

Drugs that inhibit Cdk2 and arrest the cell cycle, such as GW8510 and the experimental cancer drug seliciclib, may reduce the sensitivity of the epithelium to many cell cycle-active antitumor agents and, therefore, represent a strategy for prevention of chemotherapy-induced alopecia. [31]

Rosmarinic acid methyl ester is a plant-derived Cdk2 inhibitor, which was shown to suppress proliferation of vascular smooth muscle cells and to reduce neointima formation in mouse restenosis model. [32]

See also the PDB gallery below showing interactions with many inhibitors (inc Purvalanol B)

Gene regulation

In melanocytic cell types, expression of the CDK2 gene is regulated by the Microphthalmia-associated transcription factor. [33] [34]

Interactions

Cyclin-dependent kinase 2 has been shown to interact with:

Overview of signal transduction pathways involved in apoptosis. Signal transduction pathways.svg
Overview of signal transduction pathways involved in apoptosis.

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

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

Cyclins are proteins that control the progression of a cell through the cell cycle by activating cyclin-dependent kinases (CDK).

<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">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">S phase</span> DNA replication phase of the cell cycle, between G1 and G2 phase

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

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

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

<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.

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 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 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.

<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.

<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">CDKN3</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase inhibitor 3 is an enzyme that in humans is encoded by the CDKN3 gene.

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 CDK inhibitor is any chemical that inhibits the function of CDKs. They are used to treat cancers by preventing overproliferation of cancer cells. The US FDA approved the first drug of this type, palbociclib (Ibrance), a CDK4/6 inhibitor, in February 2015, for use in postmenopausal women with breast cancer that is estrogen receptor positive and HER2 negative. While there are multiple cyclin/CDK complexes regulating the cell cycle, CDK inhibitors targeting CDK4/6 have been the most successful; four CDK4/6 inhibitors have been FDA approved. No inhibitors targeting other CDKs have been FDA approved, but several compounds are in clinical trials.

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.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000123374 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000025358 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Tsai LH, Harlow E, Meyerson M (September 1991). "Isolation of the human cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated p33 kinase". Nature. 353 (6340): 174–7. Bibcode:1991Natur.353..174T. doi:10.1038/353174a0. PMID   1653904. S2CID   4358953.
  6. ↑ "Entrez Gene: CDK2 cyclin-dependent kinase 2".
  7. 1 2 3 Echalier A, Endicott JA, Noble ME (March 2010). "Recent developments in cyclin-dependent kinase biochemical and structural studies". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1804 (3): 511–9. doi:10.1016/j.bbapap.2009.10.002. PMID   19822225.
  8. ↑ "Entrez Gene: CDK2 cyclin-dependent kinase 2".
  9. ↑ Berthet C, Aleem E, Coppola V, Tessarollo L, Kaldis P (October 2003). "Cdk2 knockout mice are viable". Current Biology. 13 (20): 1775–85. Bibcode:2003CBio...13.1775B. doi: 10.1016/j.cub.2003.09.024 . PMID   14561402. S2CID   14320937.
  10. 1 2 3 4 Satyanarayana A, Kaldis P (August 2009). "Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms". Oncogene. 28 (33): 2925–39. doi: 10.1038/onc.2009.170 . PMID   19561645.
  11. 1 2 3 Su TT, Stumpff J (March 2004). "Promiscuity rules? The dispensability of cyclin E and Cdk2". Science's STKE. 2004 (224): pe11. doi:10.1126/stke.2242004pe11. PMC   3242733 . PMID   15026579.
  12. 1 2 3 4 Wood DJ, Korolchuk S, Tatum NJ, Wang LZ, Endicott JA, Noble ME, Martin MP (November 2018). "Differences in the Conformational Energy Landscape of CDK1 and CDK2 Suggest a Mechanism for Achieving Selective CDK Inhibition". Cell Chemical Biology. 26 (1): 121–130.e5. doi:10.1016/j.chembiol.2018.10.015. PMC   6344228 . PMID   30472117.
  13. ↑ PDB: 1FIN ​; Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz J, Massagué J, Pavletich NP (July 1995). "Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex". Nature. 376 (6538): 313–20. Bibcode:1995Natur.376..313J. doi:10.1038/376313a0. PMID   7630397. S2CID   4361179.
  14. ↑ Malumbres M (2014-06-30). "Cyclin-dependent kinases". Genome Biology. 15 (6): 122. doi: 10.1186/gb4184 . PMC   4097832 . PMID   25180339.
  15. ↑ PDB: 1W98 ​; Honda R, Lowe ED, Dubinina E, Skamnaki V, Cook A, Brown NR, Johnson LN (February 2005). "The structure of cyclin E1/CDK2: implications for CDK2 activation and CDK2-independent roles". The EMBO Journal. 24 (3): 452–63. doi:10.1038/sj.emboj.7600554. PMC   548659 . PMID   15660127.
  16. ↑ Bartek J, Lukas C, Lukas J (October 2004). "Checking on DNA damage in S phase". Nature Reviews. Molecular Cell Biology. 5 (10): 792–804. doi:10.1038/nrm1493. PMID   15459660. S2CID   33560392.
  17. 1 2 Caruso JA, Duong MT, Carey JP, Hunt KK, Keyomarsi K (October 2018). "Low-Molecular-Weight Cyclin E in Human Cancer: Cellular Consequences and Opportunities for Targeted Therapies". Cancer Research. 78 (19): 5481–5491. doi:10.1158/0008-5472.can-18-1235. PMC   6168358 . PMID   30194068.
  18. 1 2 Giacinti C, Giordano A (August 2006). "RB and cell cycle progression". Oncogene. 25 (38): 5220–7. doi: 10.1038/sj.onc.1209615 . PMID   16936740.
  19. ↑ Cobrinik D (April 2005). "Pocket proteins and cell cycle control". Oncogene. 24 (17): 2796–809. doi: 10.1038/sj.onc.1208619 . PMID   15838516.
  20. ↑ The molecular basis of cancer. Mendelsohn, John, 1936-, Gray, Joe W.,, Howley, Peter M.,, Israel, Mark A.,, Thompson, Craig (Craig B.) (Fourth ed.). Philadelphia, PA. 2015. ISBN   978-1-4557-4066-6. OCLC   870870610.{{cite book}}: CS1 maint: location missing publisher (link) CS1 maint: others (link)
  21. ↑ Zhao J, Kennedy BK, Lawrence BD, Barbie DA, Matera AG, Fletcher JA, Harlow E (September 2000). "NPAT links cyclin E-Cdk2 to the regulation of replication-dependent histone gene transcription". Genes & Development. 14 (18): 2283–97. doi:10.1101/gad.827700. PMC   316937 . PMID   10995386.
  22. ↑ Gopinathan L, Tan SL, Padmakumar VC, Coppola V, Tessarollo L, Kaldis P (July 2014). "Loss of Cdk2 and cyclin A2 impairs cell proliferation and tumorigenesis". Cancer Research. 74 (14): 3870–9. doi:10.1158/0008-5472.CAN-13-3440. PMC   4102624 . PMID   24802190.
  23. ↑ Xia P, Liu Y, Chen J, Coates S, Liu D, Cheng Z (October 2018). "Inhibition of cyclin-dependent kinase 2 protects against doxorubicin-induced cardiomyocyte apoptosis and cardiomyopathy". The Journal of Biological Chemistry. 293 (51): 19672–19685. doi: 10.1074/jbc.ra118.004673 . PMC   6314117 . PMID   30361442.
  24. 1 2 Whittaker SR, Mallinger A, Workman P, Clarke PA (May 2017). "Inhibitors of cyclin-dependent kinases as cancer therapeutics". Pharmacology & Therapeutics. 173: 83–105. doi:10.1016/j.pharmthera.2017.02.008. PMC   6141011 . PMID   28174091.
  25. ↑ Cicenas J, Kalyan K, Sorokinas A, Stankunas E, Levy J, Meskinyte I, Stankevicius V, Kaupinis A, Valius M (June 2015). "Roscovitine in cancer and other diseases". Annals of Translational Medicine. 3 (10): 135. doi:10.3978/j.issn.2305-5839.2015.03.61. PMC   4486920 . PMID   26207228.
  26. ↑ Brown NR, Korolchuk S, Martin MP, Stanley WA, Moukhametzianov R, Noble ME, Endicott JA (April 2015). "CDK1 structures reveal conserved and unique features of the essential cell cycle CDK". Nature Communications. 6: 6769. Bibcode:2015NatCo...6.6769B. doi:10.1038/ncomms7769. PMC   4413027 . PMID   25864384.
  27. ↑ Rastelli G, Anighoro A, Chripkova M, Carrassa L, Broggini M (2014-06-09). "Structure-based discovery of the first allosteric inhibitors of cyclin-dependent kinase 2". Cell Cycle. 13 (14): 2296–305. doi:10.4161/cc.29295. PMC   4111683 . PMID   24911186.
  28. ↑ Pellerano M, Tcherniuk S, Perals C, Ngoc Van TN, Garcin E, Mahuteau-Betzer F, Teulade-Fichou MP, Morris MC (August 2017). "Targeting Conformational Activation of CDK2 Kinase". Biotechnology Journal. 12 (8): 1600531. doi:10.1002/biot.201600531. PMID   28430399.
  29. 1 2 Singh R, Bhardwaj VK, Sharma J, Das P, Purohit R (March 2021). "Identification of selective cyclin-dependent kinase 2 inhibitor from the library of pyrrolone-fused benzosuberene compounds: an in silico exploration". Journal of Biomolecular Structure and Dynamics. 40 (17): 7693–7701. doi:10.1080/07391102.2021.1900918. PMID   33749525. S2CID   232309609.
  30. ↑ Levkau B, Koyama H, Raines EW, Clurman BE, Herren B, Orth K, Roberts JM, Ross R (March 1998). "Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade". Molecular Cell. 1 (4): 553–63. doi: 10.1016/S1097-2765(00)80055-6 . PMID   9660939.
  31. ↑ Davis ST, Benson BG, Bramson HN, Chapman DE, Dickerson SH, Dold KM, Eberwein DJ, Edelstein M, Frye SV, Gampe RT, Griffin RJ, Harris PA, Hassell AM, Holmes WD, Hunter RN, Knick VB, Lackey K, Lovejoy B, Luzzio MJ, Murray D, Parker P, Rocque WJ, Shewchuk L, Veal JM, Walker DH, Kuyper LF (January 2001). "Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors". Science. 291 (5501): 134–7. Bibcode:2001Sci...291..134D. doi:10.1126/science.291.5501.134. PMID   11141566. (Retracted, see doi:10.1126/science.298.5602.2327b, PMID   12526115 . If this is an intentional citation to a retracted paper, please replace {{ retracted |...}} with {{ retracted |...|intentional=yes}}.)
  32. ↑ Liu R, Heiss EH, Waltenberger B, Blažević T, Schachner D, Jiang B, Krystof V, Liu W, Schwaiger S, Peña-Rodríguez LM, Breuss JM, Stuppner H, Dirsch VM, Atanasov AG (April 2018). "Constituents of Mediterranean Spices Counteracting Vascular Smooth Muscle Cell Proliferation: Identification and Characterization of Rosmarinic Acid Methyl Ester as a Novel Inhibitor". Molecular Nutrition & Food Research. 62 (7): e1700860. doi:10.1002/mnfr.201700860. PMID   29405576. S2CID   4634007.
  33. ↑ Du J, Widlund HR, Horstmann MA, Ramaswamy S, Ross K, Huber WE, Nishimura EK, Golub TR, Fisher DE (December 2004). "Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF". Cancer Cell. 6 (6): 565–76. doi: 10.1016/j.ccr.2004.10.014 . PMID   15607961.
  34. ↑ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (December 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research. 21 (6): 665–76. doi: 10.1111/j.1755-148X.2008.00505.x . PMID   19067971. S2CID   24698373.
  35. ↑ Chen Y, Farmer AA, Chen CF, Jones DC, Chen PL, Lee WH (July 1996). "BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner". Cancer Research. 56 (14): 3168–72. PMID   8764100.
  36. ↑ Ruffner H, Jiang W, Craig AG, Hunter T, Verma IM (July 1999). "BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site". Molecular and Cellular Biology. 19 (7): 4843–54. doi:10.1128/MCB.19.7.4843. PMC   84283 . PMID   10373534.
  37. ↑ Wang H, Shao N, Ding QM, Cui J, Reddy ES, Rao VN (July 1997). "BRCA1 proteins are transported to the nucleus in the absence of serum and splice variants BRCA1a, BRCA1b are tyrosine phosphoproteins that associate with E2F, cyclins and cyclin dependent kinases". Oncogene. 15 (2): 143–57. doi: 10.1038/sj.onc.1201252 . PMID   9244350.
  38. ↑ Shintani S, Ohyama H, Zhang X, McBride J, Matsuo K, Tsuji T, Hu MG, Hu G, Kohno Y, Lerman M, Todd R, Wong DT (September 2000). "p12(DOC-1) is a novel cyclin-dependent kinase 2-associated protein". Molecular and Cellular Biology. 20 (17): 6300–7. doi:10.1128/MCB.20.17.6300-6307.2000. PMC   86104 . PMID   10938106.
  39. 1 2 Connor MK, Kotchetkov R, Cariou S, Resch A, Lupetti R, Beniston RG, Melchior F, Hengst L, Slingerland JM (January 2003). "CRM1/Ran-mediated nuclear export of p27(Kip1) involves a nuclear export signal and links p27 export and proteolysis". Molecular Biology of the Cell. 14 (1): 201–13. doi:10.1091/mbc.E02-06-0319. PMC   140238 . PMID   12529437.
  40. 1 2 Rosner M, Hengstschläger M (November 2004). "Tuberin binds p27 and negatively regulates its interaction with the SCF component Skp2". The Journal of Biological Chemistry. 279 (47): 48707–15. doi: 10.1074/jbc.M405528200 . PMID   15355997.
  41. ↑ Youn CK, Cho HJ, Kim SH, Kim HB, Kim MH, Chang IY, Lee JS, Chung MH, Hahm KS, You HJ (February 2005). "Bcl-2 expression suppresses mismatch repair activity through inhibition of E2F transcriptional activity". Nature Cell Biology. 7 (2): 137–47. doi:10.1038/ncb1215. PMID   15619620. S2CID   42766325.
  42. ↑ Porter LA, Kong-Beltran M, Donoghue DJ (September 2003). "Spy1 interacts with p27Kip1 to allow G1/S progression". Molecular Biology of the Cell. 14 (9): 3664–74. doi:10.1091/mbc.E02-12-0820. PMC   196558 . PMID   12972555.
  43. 1 2 Law BK, Chytil A, Dumont N, Hamilton EG, Waltner-Law ME, Aakre ME, Covington C, Moses HL (December 2002). "Rapamycin potentiates transforming growth factor beta-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells". Molecular and Cellular Biology. 22 (23): 8184–98. doi:10.1128/mcb.22.23.8184-8198.2002. PMC   134072 . PMID   12417722.
  44. ↑ Yeh CT, Lu SC, Chao CH, Chao ML (May 2003). "Abolishment of the interaction between cyclin-dependent kinase 2 and Cdk-associated protein phosphatase by a truncated KAP mutant". Biochemical and Biophysical Research Communications. 305 (2): 311–4. doi:10.1016/s0006-291x(03)00757-5. PMID   12745075.
  45. ↑ Hannon GJ, Casso D, Beach D (March 1994). "KAP: a dual specificity phosphatase that interacts with cyclin-dependent kinases". Proceedings of the National Academy of Sciences of the United States of America. 91 (5): 1731–5. Bibcode:1994PNAS...91.1731H. doi: 10.1073/pnas.91.5.1731 . PMC   43237 . PMID   8127873.
  46. 1 2 Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ (November 1993). "The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases". Cell. 75 (4): 805–16. doi: 10.1016/0092-8674(93)90499-g . PMID   8242751.
  47. ↑ Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ, Timchenko NA (October 2001). "C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4". Molecular Cell. 8 (4): 817–28. doi: 10.1016/s1097-2765(01)00366-5 . PMID   11684017.
  48. ↑ Sweeney C, Murphy M, Kubelka M, Ravnik SE, Hawkins CF, Wolgemuth DJ, Carrington M (January 1996). "A distinct cyclin A is expressed in germ cells in the mouse". Development. 122 (1): 53–64. doi:10.1242/dev.122.1.53. PMID   8565853.
  49. ↑ Yang R, Morosetti R, Koeffler HP (March 1997). "Characterization of a second human cyclin A that is highly expressed in testis and in several leukemic cell lines". Cancer Research. 57 (5): 913–20. PMID   9041194.
  50. ↑ Müller-Tidow C, Wang W, Idos GE, Diederichs S, Yang R, Readhead C, Berdel WE, Serve H, Saville M, Watson R, Koeffler HP (April 2001). "Cyclin A1 directly interacts with B-myb and cyclin A1/cdk2 phosphorylate B-myb at functionally important serine and threonine residues: tissue-specific regulation of B-myb function". Blood. 97 (7): 2091–7. doi: 10.1182/blood.v97.7.2091 . PMID   11264176.
  51. ↑ Brown NR, Noble ME, Endicott JA, Johnson LN (November 1999). "The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases". Nature Cell Biology. 1 (7): 438–43. doi:10.1038/15674. PMID   10559988. S2CID   17988582.
  52. 1 2 3 Shanahan F, Seghezzi W, Parry D, Mahony D, Lees E (February 1999). "Cyclin E associates with BAF155 and BRG1, components of the mammalian SWI-SNF complex, and alters the ability of BRG1 to induce growth arrest". Molecular and Cellular Biology. 19 (2): 1460–9. doi:10.1128/mcb.19.2.1460. PMC   116074 . PMID   9891079.
  53. 1 2 McKenzie PP, Danks MK, Kriwacki RW, Harris LC (July 2003). "P21Waf1/Cip1 dysfunction in neuroblastoma: a novel mechanism of attenuating G0-G1 cell cycle arrest". Cancer Research. 63 (13): 3840–4. PMID   12839982.
  54. ↑ Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, Nishimoto T, Morgan DO, Franza BR, Roberts JM (September 1992). "Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle". Science. 257 (5077): 1689–94. Bibcode:1992Sci...257.1689K. doi:10.1126/science.1388288. PMID   1388288.
  55. ↑ Mayer C, Zhao J, Yuan X, Grummt I (February 2004). "mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability". Genes & Development. 18 (4): 423–34. doi:10.1101/gad.285504. PMC   359396 . PMID   15004009.
  56. ↑ Boudrez A, Beullens M, Groenen P, Van Eynde A, Vulsteke V, Jagiello I, Murray M, Krainer AR, Stalmans W, Bollen M (August 2000). "NIPP1-mediated interaction of protein phosphatase-1 with CDC5L, a regulator of pre-mRNA splicing and mitotic entry". The Journal of Biological Chemistry. 275 (33): 25411–7. doi: 10.1074/jbc.M001676200 . PMID   10827081.
  57. ↑ Henneke G, Koundrioukoff S, Hübscher U (July 2003). "Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation". Oncogene. 22 (28): 4301–13. doi: 10.1038/sj.onc.1206606 . PMID   12853968.
  58. ↑ Méndez J, Zou-Yang XH, Kim SY, Hidaka M, Tansey WP, Stillman B (March 2002). "Human origin recognition complex large subunit is degraded by ubiquitin-mediated proteolysis after initiation of DNA replication". Molecular Cell. 9 (3): 481–91. doi: 10.1016/s1097-2765(02)00467-7 . PMID   11931757.
  59. 1 2 Yam CH, Ng RW, Siu WY, Lau AW, Poon RY (January 1999). "Regulation of cyclin A-Cdk2 by SCF component Skp1 and F-box protein Skp2". Molecular and Cellular Biology. 19 (1): 635–45. doi:10.1128/mcb.19.1.635. PMC   83921 . PMID   9858587.
  60. ↑ Ono T, Kitaura H, Ugai H, Murata T, Yokoyama KK, Iguchi-Ariga SM, Ariga H (October 2000). "TOK-1, a novel p21Cip1-binding protein that cooperatively enhances p21-dependent inhibitory activity toward CDK2 kinase". The Journal of Biological Chemistry. 275 (40): 31145–54. doi: 10.1074/jbc.M003031200 . PMID   10878006.
  61. 1 2 Cheng A, Kaldis P, Solomon MJ (November 2000). "Dephosphorylation of human cyclin-dependent kinases by protein phosphatase type 2C alpha and beta 2 isoforms". The Journal of Biological Chemistry. 275 (44): 34744–9. doi: 10.1074/jbc.M006210200 . PMID   10934208.
  62. ↑ Leng X, Noble M, Adams PD, Qin J, Harper JW (April 2002). "Reversal of growth suppression by p107 via direct phosphorylation by cyclin D1/cyclin-dependent kinase 4". Molecular and Cellular Biology. 22 (7): 2242–54. doi:10.1128/mcb.22.7.2242-2254.2002. PMC   133692 . PMID   11884610.
  63. ↑ Lacy S, Whyte P (May 1997). "Identification of a p130 domain mediating interactions with cyclin A/cdk 2 and cyclin E/cdk 2 complexes". Oncogene. 14 (20): 2395–406. doi: 10.1038/sj.onc.1201085 . PMID   9188854.
  64. ↑ Marti A, Wirbelauer C, Scheffner M, Krek W (May 1999). "Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation". Nature Cell Biology. 1 (1): 14–9. doi:10.1038/8984. PMID   10559858. S2CID   8884226.

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