Contents 1 Function 2 Regulation 2.1 Transcription 2.2 Translation 2.3 Proteolysis 2.4 Nuclear export 2.5 MicroRNA regulation 3 Role in cancer 3.1 Proliferation 3.2 Metastasis 3.3 MicroRNA regulation 4 Regulation in specific cancers 4.1 Breast 4.2 Prostate 5 Clinical significance 5.1 Prognostic value 5.2 Correlation to treatment response 5.3 Value as a therapeutic target 5.3.1 Use of microRNAs for therapy 6 Role in Regeneration 7 Interactions 8 See also 9 References 10 Further reading 11 External links

Function[edit] The p27Kip1 gene has a DNA sequence similar to other members of the "Cip/Kip" family which include the p21Cip1/Waf1 and p57Kip2 genes. In addition to this structural similarity the "Cip/Kip" proteins share the functional characteristic of being able to bind several different classes of Cyclin and Cdk molecules. For example, p27Kip1 binds to cyclin D either alone, or when complexed to its catalytic subunit CDK4. In doing so p27Kip1 inhibits the catalytic activity of Cdk4, which means that it prevents Cdk4 from adding phosphate residues to its principal substrate, the retinoblastoma (pRb) protein. Increased levels of the p27Kip1 protein typically cause cells to arrest in the G1 phase of the cell cycle. Likewise, p27Kip1 is able to bind other Cdk proteins when complexed to cyclin subunits such as Cyclin E/Cdk2 and Cyclin A/Cdk2.

Regulation[edit] In general, extracellular growth factors which promote cell division reduce transcription and translation of p27Kip1. Also, increased synthesis of CDk4,6/cyclin D causes binding of p27 to this complex, sequestering it from binding to the CDk2/cyclin E complex. Furthermore, an active CDK2/cyclin E complex will phosphorylate p27 and tag p27 for ubiquitination.[6] A mutation of this gene may lead to loss of control over the cell cycle leading to uncontrolled cellular proliferation.[7][8][9] Loss of p27 expression has been observed in metastatic canine mammary carcinomas.[10][11][12] Decreased TGF-beta signalling has been suggested to cause loss of p27 expression in this tumor type.[13] A structured cis-regulatory element has been found in the 5' UTR of the P27 mRNA where it is thought to regulate translation relative to cell cycle progression.[14] P27 regulation is accomplished by two different mechanisms. In the first its concentration is changed by the individual rates of transcription, translation, and proteolysis. P27 can also be regulated by changing its subcellular location [15] Both mechanisms act to reduce levels of p27, allowing for the activation of Cdk1 and Cdk2, and for the cell to begin progressing through the cell cycle. Transcription[edit] Transcription of the CDKN1B gene is activated by Forkhead box class O family (FoxO) proteins which also acts downstream to promote p27 nuclear localization and decrease levels of COP9 subunit 5(COPS5) which helps in the degradation of p27.[16] Transcription for p27 is activated by FoxO in response to cytokines, promyelocytic leukaemia proteins, and nuclear Akt signaling.[16] P27 transcription has also been linked to another tumor suppressor gene, MEN1, in pancreatic islet cells where it promotes CDKN1B expression.[16] Translation[edit] Translation of CDKN1B reaches its maximum during quiescence and early G1.[16] Translation is regulated by polypyrimidine tract-binding protein(PTB), ELAVL1, ELAVL4, and microRNAs.[16] PTB acts by binding CDKN1b IRES to increase translation and when PTB levels decrease, G1 phase is shortened.[16] ELAVL1 and ELAVL4 also bind to CDKN1B IRES but they do so in order to decrease translation and so depletion of either results in G1 arrest.[16] Proteolysis[edit] Degradation of the p27 protein occurs as cells exit quiescence and enter G1.[16] Protein levels continue to fall rapidly as the cell continues through G1 and enters S phase. One of the most understood mechanisms for p27 proteolysis is the polyubiquitylation of p27 by the SCFSKP2 kinase associated protein 1 (Skp1) and 2 (Skp2).[16] SKP1 and Skp2 degrades p27 after it has been phosphorylated at threonine 187 (Thr187) by either activating cyclin E- or cyclin A-CDK2. Skp2 is mainly responsible for the degradation of p27 levels that continues through S phase.[17] However it is rarely expressed in early G1 where p27 levels first begin to decrease. During early G1 proteolysis of p27 is regulated by KIP1 Ubiquitylation Promoting Complex (KPC) which binds to its CDK inhibitory domain.[18] P27 also has three Cdk-inhibited tyrosines at residues 74, 88, and 89.[16] Of these, Tyr74 is of special interest because it is specific to p27-type inhibitors.[16] Nuclear export[edit] Alternatively to the transcription, translation, and protelytic method of regulation, p27 levels can also be changed by exporting p27 to the cytoplasm. This occurs when p27 is phosphorylated on Ser(10) which allows for CRM1, a nuclear export carrier protein, to bind to and remove p27 from the nucleus.[19] Once p27 is excluded from the nucleus it cannot inhibit the cell’s growth. In the cytoplasm it may be degraded entirely or retained.[15] This step occurs very early when the cell is exiting the quiescent phase and thus is independent of Skp2 degradation of p27.[19] MicroRNA regulation[edit] Because p27 levels can be moderated at the translational level, it has been proposed that p27 may be regulated by miRNAs. Recent research has suggested that both miR-221 and miR-222 control p27 levels although the pathways are not well understood.[15]

Role in cancer[edit] Proliferation[edit] P27 is considered a tumor suppressor because of its function as a regulator of the cell cycle.[16] In cancers it is often inactivated via impaired synthesis, accelerated degradation, or mislocalization.[16] Inactivation of p27 is generally accomplished post-transcription by the oncogenic activation of various pathways including receptor tyrosine kinases (RTK), phosphatilidylinositol 3-kinase (PI3K), SRC, or Ras-mitogen activated protein kinase(MAPK).[16] These act to accelerate the proteolysis of the p27 protein and allow the cancer cell to undergo rapid division and uncontrolled proliferation.[16] When p27 is phosphorylated by Src at tyrosine 74 or 88 it ceases to inhibit cyclinE-cdk2.[20] Src was also shown to reduce the half life of p27 meaning it is degraded faster.[20] Many epithelial cancers are known to overexpress EGFR which plays a role in the proteolysis of p27 and in Ras-driven proteolysis.[16] Non-epithelial cancers use different pathways to inactivate p27.[16] Many cancer cells also upregulate Skp2 which is known to play an active role in the proteolysis of p27[17] As a result, Skp2 is inversely related to p27 levels and directly correlates with tumor grade in many malignancies.[17] Metastasis[edit] In cancer cells, p27 can also be mislocalized to the cytoplasm in order to facilitate metastasis. The mechanisms by which it acts on motility differ between cancers. In hepatocellular carcinoma cells p27 co-localizes with actin fibers to act on GTPase Rac and induce cell migration.[21] In breast cancer cytoplasmic p27 reduced RHOA activity which increased a cell’s propensity for motility.[22] This role for p27 may indicate why cancer cells rarely fully inactivate or delete p27. By retaining p27 in some capacity it can be exported to the cytoplasm during tumorgenesis and manipulated to aid in metastasis. 70% of metastatic melanomas were shown to exhibit cytoplasmic p27, while in benign melanomas p27 remained localized to the nucleus.[23] P27 is misplaced to the cytoplasm by the MAP2K, Ras, and Akt pathways although the mechanisms are not entirely understood.[24][25][26] Additionally, phosphorylation of p27 at T198 by RSK1 has been shown to mislocalize p27 to the cytoplasm as well as inhibit the RhoA pathway.[27] Because inhibition of RhoA results in a decrease in both stress fibers and focal adhesion, cell motility is increased.[28] P27 can also be exported to the cytoplasm by oncogenic activation of the P13K pathway.[28] Thus, mislocalization of p27 to the cytoplasm in cancer cells allows them to proliferate unchecked and provides for increased motility. In contrast to these results, p27 has also been shown to be an inhibitor of migration in sarcoma cells.[29] In these cells, p27 bound to stathmin which prevents stathmin from binding to tubulin and thus polymerization of microtubules increased and cell motility decreased.[29] MicroRNA regulation[edit] Studies of various cell lines including glioblastoma cell lines, three prostate cancer cell lines, and a breast tumor cell line showed that suppressing miR-221 and miR-22 expression resulted in p27-dependent G1 growth arrest[15] Then when p27 was knocked down, cell growth resumed indicating a strong role for miRNA regulated p27.[15] Studies in patients have demonstrated an inverse correlation between miR-221&22 and p27 protein levels. Additionally nearby healthy tissue showed high expression of the p27 protein while miR-221&22 concentrations were low.[15]

Regulation in specific cancers[edit] In most cancers reduced levels of nuclear p27 are correlated with increased tumor size, increased tumor grade, and a higher propensity for metastasis. However the mechanisms by which levels of p27 are regulated vary between cancers. Breast[edit] In breast cancer, Src activation has been shown to correlate with low levels of p27[20] Breast cancers that were Estrogen receptor negative and progesterone receptor negative were more likely to display low levels of p27 and more likely to have a high tumor grade.[20] Similarly, breast cancer patients with BRCA1/2 mutations were more likely to have low levels of p27.[30] Prostate[edit] A mutation in the CDKN1B gene has been linked to an increased risk for hereditary prostate cancer in humans.[31]

Clinical significance[edit] Prognostic value[edit] Several studies have demonstrated that reduced p27 levels indicate a poorer patient prognosis.[16] However, because of the dual, contrasting roles p27 plays in cancer (as an inhibitor of growth and as a mechanism for metastasis) low levels of p27 may demonstrate that a cancer is not aggressive and will remain benign.[16] In ovarian cancer, p27 negative tumors progressed in 23 months compared to 85 months in p27 positive tumors and thus could be used as a prognostic marker.[32] Similar studies have correlated low levels of p27 with a worse prognosis in breast cancer.[33] Colorectal carcinomas that lacked p27 were shown to have increased p27-specific proteolysis and a median survival of only 69 months compared to 151 months for patients with high or normal levels of p27.[34] The authors proposed clinicians could use patient specific levels of p27 to determine who would benefit from adjuvant therapy.[34] Similar correlations were observed in patients with non-small cell lung cancer,[35] those with colon,[35] and prostate cancer.[36] So far studies have only evaluated the prognostic value of p27 retrospectively and a standardized scoring system has not been established.[16] However it has been proposed that clinicians should evaluate a patient’s p27 levels in order to determine if they will be responsive to certain chemotoxins which target fast growing tumors where p27 levels are low.[16] Or in contrast, if p27 levels are found to be high in a patient’s cancer, their risk for metastasis is higher and the physician can make an informed decision about their treatment plan.[16] Because p27 levels are controlled post-transcriptionally, proteomic surveys can be used to establish and monitor a patient’s individual levels which aids in the future of individualized medicine. The following cancers have been demonstrated to have an inverse correlation with p27 expression and prognosis: oro-pharyngo-laryngeal, oesophageal, gastric, colon, lung, melanoma, glioma, breast cancer, prostate, lymphoma, leukemia.[17] Correlation to treatment response[edit] P27 may also allow clinicians to better select an appropriate treatment for a patient. For example, patients with non-small cell lung cancer who were treated with platinum based chemotherapy showed reduced survival if they had low levels of p27.[37] Similarly low levels of p27 correlated with poor results from adjuvant chemotherapy in breast cancer patients.[38] Value as a therapeutic target[edit] P27 has been explored as a potential target for cancer therapy because its levels are highly correlated to patient prognosis.[39] This is true for a wide spectrum of cancers including colon, breast, prostate, lung, liver, stomach, and bladder.[39] Use of microRNAs for therapy[edit] Because of the role miRNAs play in p27 regulation, research is underway to determine if antagomiRs that block the activity of the miR221&222 and allow for p27 cell grow inhibition to take place could act as therapeutic cancer drugs.[15]

Role in Regeneration[edit] Knockdown of CDKN1B stimulates regeneration of cochlear hair cells in mice. Since CDKN1B prevents cells from entering the cell cycle, inhibition of the protein could cause re-entry and subsequent division. In mammals where regeneration of cochlear hair cells normally does not occur, this inhibition could help regrow damaged cells who are otherwise incapable of proliferation. In fact, when the CDKN1B gene is disrupted in adult mice, hair cells of the organ of Corti proliferate, while those in control mice do not. Lack of CDKN1B expression appears to release the hair cells from natural cell-cycle arrest.[40][41] Because hair cell death in the human cochlea is a major cause of hearing loss, the CDKN1B protein could be an important factor in the clinical treatment of deafness.

Interactions[edit] CDKN1B has been shown to interact with: AKT1,[42] CKS1B,[43][44] Cyclin D3,[45][46][47] Cyclin E1,[48][49] Cyclin-dependent kinase 2,[48][50][51][52][53] Cyclin-dependent kinase 4,[45][54] Grb2,[55] NUP50[56] SKP2,[42][43][44] SPDYA,[50] and XPO1.[48][57] Overview of signal transduction pathways involved in apoptosis.

See also[edit] Sic1 (homologue in Saccharomyces cerevisiae) P21waf-1 (another CDK inhibitor) Hyaluronic acid synthase Hyaluronidase

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PMID 15619620.  ^ Law BK, Chytil A, Dumont N, Hamilton EG, Waltner-Law ME, Aakre ME, Covington C, Moses HL (2002). "Rapamycin potentiates transforming growth factor beta-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells". Mol. Cell. Biol. 22 (23): 8184–98. doi:10.1128/MCB.22.23.8184-8198.2002. PMC 134072 . PMID 12417722.  ^ Rosner M, Hengstschläger M (2004). "Tuberin binds p27 and negatively regulates its interaction with the SCF component Skp2". J. Biol. Chem. 279 (47): 48707–15. doi:10.1074/jbc.M405528200. PMID 15355997.  ^ Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N, Slingerland JM (2000). "Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells". Proc. Natl. Acad. Sci. U.S.A. 97 (16): 9042–6. doi:10.1073/pnas.160016897. PMC 16818 . PMID 10908655.  ^ Sugiyama Y, Tomoda K, Tanaka T, Arata Y, Yoneda-Kato N, Kato J (2001). "Direct binding of the signal-transducing adaptor Grb2 facilitates down-regulation of the cyclin-dependent kinase inhibitor p27Kip1". J. Biol. Chem. 276 (15): 12084–90. doi:10.1074/jbc.M010811200. PMID 11278754.  ^ Smitherman M, Lee K, Swanger J, Kapur R, Clurman BE (2000). "Characterization and targeted disruption of murine Nup50, a p27(Kip1)-interacting component of the nuclear pore complex". Mol. Cell. Biol. 20 (15): 5631–42. doi:10.1128/MCB.20.15.5631-5642.2000. PMC 86029 . PMID 10891500.  ^ Ishida N, Hara T, Kamura T, Yoshida M, Nakayama K, Nakayama KI (2002). "Phosphorylation of p27Kip1 on serine 10 is required for its binding to CRM1 and nuclear export". J. Biol. Chem. 277 (17): 14355–8. doi:10.1074/jbc.C100762200. PMID 11889117. 

Further reading[edit] Marone M, Bonanno G, Rutella S, Leone G, Scambia G, Pierelli L (2003). "Survival and cell cycle control in early hematopoiesis: role of bcl-2, and the cyclin dependent kinase inhibitors P27 and P21". Leuk. Lymphoma. 43 (1): 51–7. doi:10.1080/10428190210195. PMID 11908736.  Hirabayashi H (2003). "[P27 expression and survival in NSCLC]". Nippon Rinsho. 60 Suppl 5: 263–6. PMID 12101669.  Bloom J, Pagano M (2003). "Deregulated degradation of the cdk inhibitor p27 and malignant transformation". Semin. Cancer Biol. 13 (1): 41–7. doi:10.1016/S1044-579X(02)00098-6. PMID 12507555.  Tokumoto M, Tsuruya K, Fukuda K, Kanai H, Kuroki S, Hirakata H, Iida M (2003). "Parathyroid cell growth in patients with advanced secondary hyperparathyroidism: vitamin D receptor and cyclin-dependent kinase inhibitors, p21 and p27". Nephrol. Dial. Transplant. 18 Suppl 3: iii9–12. doi:10.1093/ndt/gfg1003. PMID 12771291.  Drexler HC (2004). "The role of p27Kip1 in proteasome inhibitor induced apoptosis". Cell Cycle. 2 (5): 438–41. doi:10.4161/cc.2.5.461. PMID 12963837.  Le XF, Pruefer F, Bast RC (2006). "HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27Kip1 via multiple signaling pathways". Cell Cycle. 4 (1): 87–95. doi:10.4161/cc.4.1.1360. PMID 15611642.  Belletti B, Nicoloso MS, Schiappacassi M, Chimienti E, Berton S, Lovat F, Colombatti A, Baldassarre G (2005). "p27(kip1) functional regulation in human cancer: a potential target for therapeutic designs". Curr. Med. Chem. 12 (14): 1589–605. doi:10.2174/0929867054367149. PMID 16022660.  Sankaranarayanan P, Schomay TE, Aiello KA, Alter O (April 2015). "Tensor GSVD of Patient- and Platform-Matched Tumor and Normal DNA Copy-Number Profiles Uncovers Chromosome Arm-Wide Patterns of Tumor-Exclusive Platform-Consistent Alterations Encoding for Cell Transformation and Predicting Ovarian Cancer Survival". PLOS ONE. 10 (4): e0121396. doi:10.1371/journal.pone.0121396. PMC 4398562 . PMID 25875127. 

External links[edit] CDKN1B human gene location in the UCSC Genome Browser. CDKN1B human gene details in the UCSC Genome Browser. v t e PDB gallery 1jsu: P27(KIP1)/CYCLIN A/CDK2 COMPLEX  v t e Cell cycle proteins Cyclin A (A1, A2) B (B1, B2, B3) D (D1, D2, D3) E (E1, E2) CDK 1 2 3 4 5 6 7 8 9 10 CDK-activating kinase CDK inhibitor INK4a/ARF (p14arf/p16, p15, p18, p19) cip/kip (p21, p27, p57) P53 p63 p73 family p53 p63 p73 Other Cdc2 Cdc25 Cdc42 Cellular apoptosis susceptibility protein E2F Maturation promoting factor Wee Cullin (CUL7) Phases and checkpoints Interphase G1 phase S phase G2 phase M phase Mitosis (Preprophase Prophase Prometaphase Metaphase Anaphase Telophase) Cytokinesis Cell cycle checkpoints Restriction point Spindle checkpoint Postreplication checkpoint Other cellular phases Apoptosis G0 phase Meiosis v t e Neoplasm: Tumor suppressor genes/proteins and Oncogenes/Proto-oncogenes Ligand Growth factors ONCO c-Sis/PDGF HGF Receptor Wnt signaling pathway TSP CDH1 Hedgehog signaling pathway TSP PTCH1 TGF beta signaling pathway TSP TGF beta receptor 2 Receptor tyrosine kinase ONCO ErbB/c-ErbB HER2/neu Her 3 c-Met c-Ret JAK-STAT signaling pathway ONCO c-Kit Flt3 Intracellular signaling P+Ps Wnt signaling pathway ONCO Beta-catenin TSP APC TGF beta signaling pathway TSP SMAD2 SMAD4 Akt/PKB signaling pathway ONCO c-Akt TSP PTEN Hippo signaling pathway TSP Neurofibromin 2/Merlin MAPK/ERK pathway ONCO c-Ras HRAS c-Raf TSP Neurofibromin 1 Other/unknown ONCO c-Src TSP Maspin Nucleus Cell cycle ONCO CDK4 Cyclin D Cyclin E TSP p53 pRb WT1 p16/p14arf DNA repair/Fanconi TSP BRCA1 BRCA2 Ubiquitin ligase ONCO CBL MDM2 TSP VHL Transcription factor ONCO AP-1 c-Fos c-Jun c-Myc TSP KLF6 Mitochondrion Apoptosis inhibitor SDHB SDHD Other/ungrouped c-Bcl-2 Notch Stathmin Retrieved from "" Categories: Genes on human chromosome 12Cell cycleTumor suppressor genes

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CDKN1B - Photos and All Basic Informations

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Protein Data BankGene NomenclatureMouse Genome InformaticsHomoloGeneGeneCardsChromosome 12 (human)ChromosomeChromosome 12 (human)Chromosome 12 (human)Genomic Location For CDKN1BGenomic Location For CDKN1BLocus (genetics)Base PairBase PairChromosome 6 (mouse)ChromosomeChromosome 6 (mouse)Genomic Location For CDKN1BGenomic Location For CDKN1BLocus (genetics)Base PairBase PairGene ExpressionGene OntologyEntrezEnsemblUniProtPubMedWikidataEnzyme InhibitorGeneProteinCIP/KIPCyclin Dependent KinaseCyclin ECyclin-dependent Kinase 2Cyclin DCyclin-dependent Kinase 4Cell CycleCell CycleCell Division CycleDNA SequenceP21P57 (gene)Cyclin DCyclin-dependent Kinase 4CatalyticPhosphateSubstrate (biochemistry)RetinoblastomaPRbG1 PhaseCyclin ECdk2Cyclin ACdk2P27 Cis-regulatory ElementMRNACell CycleSRC (gene)Regeneration (biology)Cell CycleHair CellHair CellOrgan Of CortiHair CellCochleaHearing LossDeafnessProtein-protein InteractionAKT1CKS1BCyclin D3Cyclin E1Cyclin-dependent Kinase 2Cyclin-dependent Kinase 4Grb2NUP50SKP2SPDYAXPO1EnlargeApoptosisSic1Saccharomyces CerevisiaeP21Hyaluronic Acid SynthaseHyaluronidaseEnsembl Genome Database ProjectEnsembl Genome Database ProjectDigital Object IdentifierPubMed IdentifierInternational Standard Book NumberSpecial:BookSources/978-0-87893-300-6Cell (journal)Digital Object IdentifierPubMed IdentifierAdrian HaydayCell (journal)Digital Object IdentifierPubMed IdentifierCell (journal)Digital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierUCSC Genome BrowserUCSC Genome BrowserTemplate:PDB GalleryTemplate Talk:PDB Gallery1jsu: P27(KIP1)/CYCLIN A/CDK2 COMPLEXTemplate:Cell Cycle ProteinsTemplate Talk:Cell Cycle ProteinsCell CycleProteinCyclinCyclin ACyclin A1Cyclin A2Cyclin BCyclin B1Cyclin B2Cyclin DCyclin D1Cyclin D2Cyclin D3Cyclin ECyclin E1Cyclin E2Cyclin-dependent KinaseCyclin-dependent Kinase 1Cyclin-dependent Kinase 2Cyclin-dependent Kinase 3Cyclin-dependent Kinase 4Cyclin-dependent Kinase 5Cyclin-dependent Kinase 6Cyclin-dependent Kinase 7Cyclin-dependent Kinase 8Cyclin-dependent Kinase 9Cyclin-dependent Kinase 10CDK-activating KinaseCyclin-dependent Kinase Inhibitor ProteinCell CycleP14arfP16CDKN2BCDKN2CCDKN2DCell CycleP21Cyclin-dependent Kinase Inhibitor 1CP53 P63 P73 FamilyP53TP63P73Cdk1Cdc25CDC42Cellular Apoptosis Susceptibility ProteinE2FMaturation Promoting FactorWee1CullinCUL7InterphaseG1 PhaseS PhaseG2 PhaseCell DivisionMitosisPreprophaseProphasePrometaphaseMetaphaseAnaphaseTelophaseCytokinesisCell Cycle CheckpointRestriction PointSpindle CheckpointPostreplication CheckpointApoptosisG0 PhaseMeiosisTemplate:Tumor Suppressor Genes And OncogenesTemplate Talk:Tumor Suppressor Genes And OncogenesNeoplasmTumor Suppressor GeneOncogeneLigand (biochemistry)Growth FactorPlatelet-derived Growth FactorHepatocyte Growth FactorReceptor (biochemistry)Wnt Signaling PathwayCDH1 (gene)Hedgehog Signaling PathwayPTCH1TGF Beta Signaling PathwayTGF Beta Receptor 2Receptor Tyrosine KinaseErbBEpidermal Growth Factor ReceptorHER2/neuERBB3C-MetRET Proto-oncogeneJAK-STAT Signaling PathwayCD117CD135Intracellular Signaling Peptides And ProteinsWnt Signaling PathwayBeta-cateninAdenomatosis Polyposis ColiTGF Beta Signaling PathwayMothers Against Decapentaplegic Homolog 2Mothers Against Decapentaplegic Homolog 4Akt/PKB Signaling PathwayAKTPTEN (gene)Hippo Signaling PathwayMerlin (protein)MAPK/ERK PathwayRas (protein)HRASC-RafNeurofibromin 1Proto-oncogene Tyrosine-protein Kinase SrcMaspinCell NucleusCell CycleCyclin-dependent Kinase 4Cyclin DCyclin EP53Retinoblastoma ProteinWT1P16 (gene)P14arfDNA RepairFanconi AnemiaBRCA1BRCA2Ubiquitin LigaseCBL (gene)Mdm2Von Hippel–Lindau Tumor SuppressorTranscription FactorAP-1 Transcription FactorC-FosC-junMycKLF6MitochondrionInhibitor Of ApoptosisSDHBSDHDBcl-2Notch SignalingStathminHelp:CategoryCategory:Genes On Human Chromosome 12Category:Cell CycleCategory:Tumor Suppressor GenesDiscussion About Edits From This IP Address [n]A List Of Edits Made From This IP Address [y]View The Content Page [c]Discussion About The Content Page [t]Edit This Page [e]Visit The Main Page [z]Guides To Browsing WikipediaFeatured Content – The Best Of WikipediaFind Background Information On Current EventsLoad A Random Article [x]Guidance On How To Use And Edit WikipediaFind Out About WikipediaAbout The Project, What You Can Do, Where To Find ThingsA List Of Recent Changes In The Wiki [r]List Of All English Wikipedia Pages Containing Links To This Page [j]Recent Changes In Pages Linked From This Page [k]Upload Files 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