Cyclin-dependent kinase 4

Last updated
CDK4
Protein CDK4 PDB 1LD2.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CDK4 , CMM3, PSK-J3, cyclin-dependent kinase 4, cyclin dependent kinase 4
External IDs OMIM: 123829; MGI: 88357; HomoloGene: 55429; GeneCards: CDK4; OMA:CDK4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1019

12567

Ensembl

ENSG00000135446

n/a

UniProt

P11802

P30285

RefSeq (mRNA)

NM_052984
NM_000075

NM_009870
NM_001355005

RefSeq (protein)

NP_000066

NP_034000
NP_001341934

Location (UCSC) Chr 12: 57.75 – 57.76 Mb n/a
PubMed search [2] [3]
Wikidata
View/Edit Human View/Edit Mouse

Cyclin-dependent kinase 4 (CDK4), also known as cell division protein kinase 4, is an enzyme that is encoded by the CDK4 gene in humans. CDK4 is a member of the cyclin-dependent kinase family, a group of serine/threonine kinases which regulate the cell cycle. [4] CDK4 regulates the G1/S transition by contributing to the phosphorylation of retinoblastoma (RB) protein, which leads to the release of protein factors like E2F1 that promote S-phase progression. [5] It is regulated by cyclins like cyclin D proteins, regulatory kinases, and cyclin kinase inhibitors (CKIs). [5] Dysregulation of the CDK4 pathway is common in many cancers, and CDK4 is a new therapeutic target in cancer treatment. [6]

Contents

Structure

The CDK4 gene is located on chromosome 12 in humans. [7] The gene is composed of 4,583 base pairs which together code for the 303 amino acid protein with a molecular mass of 33,730 Da. [7] [8] All CDK proteins, including CDK4, have two lobes: the smaller N-terminal lobe (which contains an inhibitory G-loop), and the C terminal lobe (which contains an activation domain and a T-loop). Between these two lobes is the serine/threonine kinase domain where ATP binds. In its completely inactive form, CDK4's T-loop blocks the ATP binding site, and the surrounding amino acid side chains prevent ATP binding. [4] The kinase's activity increases when it dimerizes with the corresponding cyclin, cyclin D, which causes a conformational change at the ATP binding site. CDK activating kinase (CAK) then phosphorylates the T172 site (located on the T-loop). [5] [9] [10] These two actions move the T-loop out of the active ATP-binding site and make ATP binding more favorable.

Notably, CDK6 is very related to CDK4 in both structure and function. They share 71% of their amino acids and both regulate the G1/S transition by phosphorylating Rb. CDK4 and 6 differ in their cellular localization and other off-pathway roles, however are commonly referred together as CDK4/6. [4]

The CDK4 protein is similar to the fungi gene products of S. cerevisiae cdc28 and S. pombe cdc2. [7]

Function

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.

CDK4 is the catalytic subunit of the protein-kinase complex CDK4-cyclin D, which plays a role in G1/S cell cycle progression. [5] During G1 phase, the cell grows and prepares for the DNA replication that occurs in the S phase. There is a G1/S checkpoint which acts as a committed step to enter S-phase. This checkpoint ensures that cells moving toward mitosis are large enough and do not have DNA damage that could be passed on to daughter cells. [11]

There are two models of CDK4 cell cycle regulation. The older model proposes that the kinase is responsible for the phosphorylation of retinoblastoma gene product (Rb). The Ser/Thr-kinase component of cyclin D-CDK4 (DC) forms complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G1/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G1 phase. In this model, CDK4 inhibits Rb, which inhibits E2F, which promotes progression into S phase.

The newer model, as proposed in a 2014 paper by Narasimha et al., The CDK4-cyclin D complex phosphorylates the retinoblastoma tumor suppressor protein (Rb) and its related proteins p107 and p130, which go on to inhibit cell cycle progression. [5] As a kinase, the CDK4 serine/threonine active site converts ATP to ADP and transfers the removed phosphate group to Rb. Rb is mono-phosphorylated in early G1 by the CDK4-cyclin D complex. When mono-phosphorylated, Rb exists as one of the 14 isoforms, which bind to protein factors like E1a, and proteins in the E2F family. [12]

The new model of CDK4 regulation posits that at the G1/S checkpoint, if a cell seems healthy, CDK2 (a different cyclin dependent kinase) inactivates Rb, and these protein factors are released back into the cell. E2F proteins then activate the transcription of genes that cause S-phase progression. [5] However, if at the G1/S checkpoint a cell detects DNA damage, it will response by activating the CDK4-cyclin D complex to mono-phosphorylate, and activate Rb. This prevents Rb from dissociating from E2F protins, which prevents them from activating the transcription of the S-phase progression genes. [12]

While CDK4 primarily regulates the cell cycle through phosphorylation of Rb, there is evidence of a secondary, more direct role independent of Rb. CDK4 may be able to directly phosphorylate transcription factors and co-regulators like Smad3, MYC, FOXM1, and MEP50 to regulate the cell cycle, survival and senescence.

Interestingly, CDK4-null mutant mice are viable, and in-vitro experiments show that cell proliferation is not significantly affected, likely due to compensatory roles played by other CDKs. However, CDK plays a significant role in cancer development. [13]

Mechanisms of regulation

CDK4 is only active during the G1-S phase, which controlled by cyclin D and CDK inhibitors. CDK activity is negatively regulated by cyclin kinase inhibitors (CKIs), which belong to one of two families. The INK4 family of CKIs are inhibitors which bind and inhibit CDK4/6, also preventing subsequent binding to cyclin D. The Cip/Kip family inhibitors are not specific to CDK4/6, and instead bind and inhibit the cyclin-CDK complex. [4]

CDK4 activity is positively regulated by cyclin D, which creates a conformational change in CDK4 that opens the active site for kinase activity. Cyclins are proteins that change concentration periodically during the cell cycle. They are extremely specific and diverse, which serves to regulate the cell cycle with precision. Cyclin D levels oscillate during the G1 phase, first increasing and accumulating, then rapidly decreasing during the transition to the S phase. [4] Cyclin D levels are stimulated by growth factors, without which cyclin D levels would stay low regardless of cell cycle stage. [13] After its role in G1 is complete, cyclin D is translocated from the nucleus to the cytoplasm in S phase, modulating the nuclear cyclin D levels, and therefore modulating the activity of CDK4 to promote the S phase transition. [4]

Clinical significance

Cancer

Cancer, or uncontrolled cell proliferation, is believed to result from disturbances to mechanisms that usually control cell proliferation (tumor suppressors) and mechanisms that normally encourage cell proliferation (proto-oncogenes). Cell cycle regulation mechanisms called checkpoints, like G1/S, are in place to prevent this uncontrolled division. [5]

Mutations in the CDK4 gene as well as in its related proteins including D-type cyclins, p16(INK4a), CDKN2A and Rb were all found to be associated with tumorigenesis of a variety of cancers, including sarcomas, gliomas, lymphomas and tumors of the mammary gland. [13] One specific point mutation of CDK4 (R24C) was first identified in melanoma patients. This mutation was introduced also in animal models and its role as a cancer driver oncogene was studied thoroughly. [13] Nowadays, deregulated CDK4 is considered to be a potential therapeutic target in some cancer types and various CDK4 inhibitors are being tested for cancer treatment in clinical trials. Multiple polyadenylation sites of this gene have been reported.

Cyclin D and CDK4/6 activities are observed to be up-regulated in certain cancers, sparking interest in the development of small-molecule inhibitors of CDK4/6. Ribociclib are US FDA approved CDK4 and CDK6 inhibitors for the treatment of estrogen receptor positive/ HER2 negative advanced breast cancer. [14]

HIV

There is some evidence that CDK4 plays a role in the HIV-1 restriction pathway in primary microphages. Cell cycle control plays a major role in determining susceptibility to HIV-1 infection. Active CDKs phosphorylate SAMHD1, deactivating the enzyme which usually can restrict HIV-1 replication. A complex formed by cyclin D2-CDK4-p21 lowers the amount of active CDK in the cell, allowing SAMHD1 to exist in its active, dephosphorylated form that restricts HIV-1 replication. [15]

Interactions

Cyclin-dependent kinase 4 has been shown to interact with:

Overview of signal transduction pathways involved in apoptosis. (CDK4 in the (pink) nucleus) Signal transduction pathways.svg
Overview of signal transduction pathways involved in apoptosis. (CDK4 in the (pink) nucleus)

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-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 repressors: 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.

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 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 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">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">Cyclin-dependent kinase 3</span> Protein-coding gene in the species Homo sapiens

Cell division protein kinase 3 is an enzyme that in humans is encoded by the CDK3 gene.

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

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 cyclin and Cdk subunits join together, the complex gets activated, allowing it 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 GRCh38: Ensembl release 89: ENSG00000135446 – Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. 1 2 3 4 5 6 Hives M, Jurecekova J, Holeckova KH, Kliment J, Sivonova MK (2023). "The driving power of the cell cycle: cyclin-dependent kinases, cyclins and their inhibitors". Bratislavske Lekarske Listy. 124 (4): 261–266. doi: 10.4149/BLL_2023_039 . PMID   36598318.
  5. 1 2 3 4 5 6 7 Baker SJ, Reddy EP (November 2012). "CDK4: A Key Player in the Cell Cycle, Development, and Cancer". Genes & Cancer. 3 (11–12): 658–669. doi:10.1177/1947601913478972. PMC   3636745 . PMID   23634254.
  6. ↑ Sobhani N, D'Angelo A, Pittacolo M, Roviello G, Miccoli A, Corona SP, et al. (April 2019). "Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer". Cells. 8 (4): 321. doi: 10.3390/cells8040321 . PMC   6523967 . PMID   30959874.
  7. 1 2 3 "Entrez Gene: CDK4 cyclin-dependent kinase 4".
  8. ↑ "CDK4 - Cyclin-dependent kinase 4 - Homo sapiens (Human) - CDK4 gene & protein".
  9. ↑ Gharbi SI, Pelletier LA, Espada A, Gutiérrez J, Sanfeliciano SM, Rauch CT, et al. (November 2022). "Crystal structure of active CDK4-cyclin D and mechanistic basis for abemaciclib efficacy". npj Breast Cancer. 8 (1): 126. doi:10.1038/s41523-022-00494-y. PMC   9709041 . PMID   36446794.
  10. ↑ Łukasik P, Załuski M, Gutowska I (March 2021). "Cyclin-Dependent Kinases (CDK) and Their Role in Diseases Development-Review". International Journal of Molecular Sciences. 22 (6): 2935. doi: 10.3390/ijms22062935 . PMC   7998717 . PMID   33805800.
  11. ↑ Weitzman MD, Wang JY (2013-01-01), "Cell Cycle: DNA Damage Checkpoints", in Lennarz WJ, Lane MD (eds.), Encyclopedia of Biological Chemistry (Second Edition), Waltham: Academic Press, pp. 410–416, ISBN   978-0-12-378631-9 , retrieved 2024-12-16
  12. 1 2 Narasimha AM, Kaulich M, Shapiro GS, Choi YJ, Sicinski P, Dowdy SF (June 2014). Davis R (ed.). "Cyclin D activates the Rb tumor suppressor by mono-phosphorylation". eLife. 3: e02872. doi: 10.7554/eLife.02872 . PMC   4076869 . PMID   24876129.
  13. 1 2 3 4 Baker SJ, Poulikakos PI, Irie HY, Parekh S, Reddy EP (2022). "CDK4: a master regulator of the cell cycle and its role in cancer". Genes & Cancer. 13: 21–45. doi:10.18632/genesandcancer.221. PMC   9426627 . PMID   36051751.
  14. ↑ "Approved Drugs > Ribociclib (Kisqali)". Food and Drug Administration . Retrieved 12 September 2017.
  15. ↑ Badia R, Pujantell M, Riveira-Muñoz E, Puig T, Torres-Torronteras J, Martí R, et al. (August 2016). "The G1/S Specific Cyclin D2 Is a Regulator of HIV-1 Restriction in Non-proliferating Cells". PLOS Pathogens. 12 (8): e1005829. doi: 10.1371/journal.ppat.1005829 . PMC   4991798 . PMID   27541004.
  16. 1 2 3 4 Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC   1847948 . PMID   17353931.
  17. ↑ Dai K, Kobayashi R, Beach D (September 1996). "Physical interaction of mammalian CDC37 with CDK4". The Journal of Biological Chemistry. 271 (36): 22030–22034. doi: 10.1074/jbc.271.36.22030 . PMID   8703009.
  18. ↑ Lamphere L, Fiore F, Xu X, Brizuela L, Keezer S, Sardet C, et al. (April 1997). "Interaction between Cdc37 and Cdk4 in human cells". Oncogene. 14 (16): 1999–2004. doi:10.1038/sj.onc.1201036. PMID   9150368. S2CID   25236893.
  19. ↑ Stepanova L, Leng X, Parker SB, Harper JW (June 1996). "Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4". Genes & Development. 10 (12): 1491–1502. doi: 10.1101/gad.10.12.1491 . PMID   8666233.
  20. 1 2 3 Lin J, Jinno S, Okayama H (April 2001). "Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence". Oncogene. 20 (16): 2000–2009. doi:10.1038/sj.onc.1204375. PMID   11360184. S2CID   25204152.
  21. 1 2 Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N, Slingerland JM (August 2000). "Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells". Proceedings of the National Academy of Sciences of the United States of America. 97 (16): 9042–9046. Bibcode:2000PNAS...97.9042C. doi: 10.1073/pnas.160016897 . PMC   16818 . PMID   10908655.
  22. 1 2 Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, et al. (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–1178. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID   16189514. S2CID   4427026.
  23. ↑ Ghavidel A, Cagney G, Emili A (September 2005). "A skeleton of the human protein interactome". Cell. 122 (6): 830–832. doi: 10.1016/j.cell.2005.09.006 . PMID   16179252. S2CID   7410135.
  24. ↑ Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, et al. (December 1994). "Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function". Genes & Development. 8 (24): 2939–2952. doi: 10.1101/gad.8.24.2939 . PMID   8001816.
  25. ↑ Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ, et al. (October 2001). "C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4". Molecular Cell. 8 (4): 817–828. doi: 10.1016/S1097-2765(01)00366-5 . PMID   11684017.
  26. 1 2 3 Sugimoto M, Nakamura T, Ohtani N, Hampson L, Hampson IN, Shimamoto A, et al. (November 1999). "Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1)". Genes & Development. 13 (22): 3027–3033. doi:10.1101/gad.13.22.3027. PMC   317153 . PMID   10580009.
  27. 1 2 3 Nasmyth K, Hunt T (December 1993). "Cell cycle. Dams and sluices". Nature. 366 (6456): 634–635. doi: 10.1038/366634a0 . PMID   8259207. S2CID   4270052.
  28. ↑ Taulés M, Rius E, Talaya D, López-Girona A, Bachs O, Agell N (December 1998). "Calmodulin is essential for cyclin-dependent kinase 4 (Cdk4) activity and nuclear accumulation of cyclin D1-Cdk4 during G1". The Journal of Biological Chemistry. 273 (50): 33279–33286. doi: 10.1074/jbc.273.50.33279 . PMID   9837900.
  29. 1 2 Coleman KG, Wautlet BS, Morrissey D, Mulheron J, Sedman SA, Brinkley P, et al. (July 1997). "Identification of CDK4 sequences involved in cyclin D1 and p16 binding". The Journal of Biological Chemistry. 272 (30): 18869–18874. doi: 10.1074/jbc.272.30.18869 . PMID   9228064.
  30. ↑ Arsenijevic T, Degraef C, Dumont JE, Roger PP, Pirson I (March 2004). "A novel partner for D-type cyclins: protein kinase A-anchoring protein AKAP95". The Biochemical Journal. 378 (Pt 2): 673–679. doi:10.1042/BJ20031765. PMC   1223988 . PMID   14641107.
  31. ↑ Zhang Q, Wang X, Wolgemuth DJ (June 1999). "Developmentally regulated expression of cyclin D3 and its potential in vivo interacting proteins during murine gametogenesis". Endocrinology. 140 (6): 2790–2800. doi:10.1210/endo.140.6.6756. PMID   10342870. S2CID   45094232.
  32. ↑ Zhang JM, Zhao X, Wei Q, Paterson BM (December 1999). "Direct inhibition of G(1) cdk kinase activity by MyoD promotes myoblast cell cycle withdrawal and terminal differentiation". The EMBO Journal. 18 (24): 6983–6993. doi:10.1093/emboj/18.24.6983. PMC   1171761 . PMID   10601020.
  33. ↑ Zhang JM, Wei Q, Zhao X, Paterson BM (February 1999). "Coupling of the cell cycle and myogenesis through the cyclin D1-dependent interaction of MyoD with cdk4". The EMBO Journal. 18 (4): 926–933. doi:10.1093/emboj/18.4.926. PMC   1171185 . PMID   10022835.
  34. ↑ Fåhraeus R, Paramio JM, Ball KL, Laín S, Lane DP (January 1996). "Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A". Current Biology. 6 (1): 84–91. doi:10.1016/S0960-9822(02)00425-6. hdl: 20.500.11820/9e95b5cc-be55-4c50-bfd9-04eb51b3e3f9 . PMID   8805225. S2CID   23024663.
  35. 1 2 Li J, Melvin WS, Tsai MD, Muscarella P (April 2004). "The nuclear protein p34SEI-1 regulates the kinase activity of cyclin-dependent kinase 4 in a concentration-dependent manner". Biochemistry. 43 (14): 4394–4399. CiteSeerX   10.1.1.386.140 . doi:10.1021/bi035601s. PMID   15065884.
  36. ↑ Xiong Y, Zhang H, Beach D (August 1993). "Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation". Genes & Development. 7 (8): 1572–1583. doi: 10.1101/gad.7.8.1572 . PMID   8101826.

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