CDKN1B

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Cyclin-dependent kinase inhibitor 1B (p27, Kip1)
Protein CDKN1B PDB 1jsu.png
PDB rendering based on 1jsu.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CDKN1B ; CDKN4; KIP1; MEN1B; MEN4; P27KIP1
External IDs OMIM600778 MGI104565 HomoloGene2999 GeneCards: CDKN1B Gene
RNA expression pattern
PBB GE CDKN1B 209112 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 1027 12576
Ensembl ENSG00000111276 ENSMUSG00000003031
UniProt P46527 P46414
RefSeq (mRNA) NM_004064 NM_009875
RefSeq (protein) NP_004055 NP_034005
Location (UCSC) Chr 12:
12.87 – 12.88 Mb
Chr 6:
134.92 – 134.93 Mb
PubMed search [1] [2]

Cyclin-dependent kinase inhibitor 1B (p27Kip1) is an enzyme inhibitor that in humans is encoded by the CDKN1B gene.[1] It encodes a protein which belongs to the Cip/Kip family of cyclin dependent kinase (Cdk) inhibitor proteins. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. It is often referred to as a cell cycle inhibitor protein because its major function is to stop or slow down the cell division cycle.

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.[2] A mutation of this gene may lead to loss of control over the cell cycle leading to uncontrolled cellular proliferation.[3][4][5] Loss of p27 expression has been observed in metastatic canine mammary carcinomas.[6][7][8] Decreased TGF-beta signalling has been suggested to cause loss of p27 expression in this tumor type.[9]

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.[10]

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 [11] 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.[12] Transcription for p27 is activated by FoxO in response to cytokines, promyelocytic leukaemia proteins, and nuclear Akt signaling.[12] P27 transcription has also been linked to another tumor suppressor gene, MEN1, in pancreatic islet cells where it promotes CDKN1B expression.[12]

Translation[edit]

Translation of CDKN1B reaches its maximum during quiescence and early G1.[12] Translation is regulated by polypyrimidine tract-binding protein(PTB), ELAVL1, ELAVL4, and microRNAs.[12] PTB acts by binding CDKN1b IRES to increase translation and when PTB levels decrease, G1 phase is shortened.[12]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.[12]

Proteolysis[edit]

Degradation of the p27 protein occurs as cells exit quiescence and enter G1.[12] 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).[12] 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.[13] 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.[14] P27 also has three Cdk-inhibited tyrosines at residues 74, 88, and 89.[12] Of these, Tyr74 is of special interest because it is specific to p27-type inhibitors.[12]

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.[15] Once p27 is excluded from the nucleus it cannot inhibit the cell’s growth. In the cytoplasm it may be degraded entirely or retained.[11] This step occurs very early when the cell is exiting the quiescent phase and thus is independent of Skp2 degradation of p27.[15]

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 miR222 control p27 levels although the pathways are not well understood.[11]

Role in cancer[edit]

Proliferation[edit]

P27 is considered a tumor suppressor because of its function as a regulator of the cell cycle.[12] In cancers it is often inactivated via impaired synthesis, accelerated degradation, or mislocalization.[12] 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).[12] These act to accelerate the proteolysis of the p27 protein and allow the cancer cell to undergo rapid division and uncontrolled proliferation.[12] When p27 is phosphorylated by Src at tyrosine 74 or 88 it ceases to inhibit cyclinE-cdk2.[16] Src was also shown to reduce the half life of p27 meaning it is degraded faster.[16] Many epithelial cancers are known to overexpress EGFR which plays a role in the proteolysis of p27 and in Ras-driven proteolysis.[12] Non-epithelial cancers use different pathways to inactivate p27.[12] Many cancer cells also upregulate Skp2 which is known to play an active role in the proteolysis of p27[13] As a result, Skp2 is inversely related to p27 levels and directly correlates with tumor grade in many malignancies.[13]

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.[17] In breast cancer cytoplasmic p27 reduced RHOA activity which increased a cell’s propensity for motility.[18]

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.[19] P27 is misplaced to the cytoplasm by the MAP2K, Ras, and Akt pathways although the mechanisms are not entirely understood.[20][21][22] Additionally, phosphorylation of p27 at T198 by RSK1 has been shown to mislocalize p27 to the cytoplasm as well as inhibit the RhoA pathway.[23] Because inhibition of RhoA results in a decrease in both stress fibers and focal adhesion, cell motility is increased.[24] P27 can also be exported to the cytoplasm by oncogenic activation of the P13K pathway.[24] 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.[25] In these cells, p27 bound to stathmin which prevents stathmin from binding to tubulin and thus polymerization of microtubules increased and cell motility decreased.[25]

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[11] Then when p27 was knocked down, cell growth resumed indicating a strong role for miRNA regulated p27.[11] 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.[11]

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[16] 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.[16] Similarly, breast cancer patients with BRAC1/2 mutations were more likely to have low levels of p27.[26]

Prostate[edit]

A mutation in the CDKN1B gene has been linked to an increased risk for hereditary prostate cancer in humans.[27]

Clinical significance[edit]

Prognostic value[edit]

Several studies have demonstrated that reduced p27 levels indicate a poorer patient prognosis.[12] 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.[12] 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.[28] Similar studies have correlated low levels of p27 with a worse prognosis in breast cancer.[29] 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.[30] The authors proposed clinicians could use patient specific levels of p27 to determine who would benefit from adjuvant therapy.[30] Similar correlations were observed in patients with non-small cell lung cancer,[31] those with colon,[31] and prostate cancer.[32]

So far studies have only evaluated the prognostic value of p27 retrospectively and a standardized scoring system has not been established.[12] 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.[12] 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.[12] 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.[13]

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.[33] Similarly low levels of p27 correlated with poor results from adjuvant chemotherapy in breast cancer patients.[34]

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.[35] This is true for a wide spectrum of cancers including colon, breast, prostate, lung, liver, stomach, and bladder.[35]

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.[11]

Interactions[edit]

CDKN1B has been shown to interact with:

Overview of signal transduction pathways involved in apoptosis.

See also[edit]

References[edit]

  1. ^ Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P, Massague J (August 1994). "Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals". Cell 78 (1): 59–66. doi:10.1016/0092-8674(94)90572-X. PMID 8033212. 
  2. ^ Cooper/ Hausman, Geoffrey/ Robert (2009). The Cell. Boston University: ASM Press. p. 669. ISBN 978-0-87893-300-6. 
  3. ^ Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Polyak K, Tsai LH, Broudy V, Perlmutter RM, Kaushansky K, Roberts JM (May 1996). "A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice". Cell 85 (5): 733–44. doi:10.1016/S0092-8674(00)81239-8. PMID 8646781. 
  4. ^ Kiyokawa H, Kineman RD, Manova-Todorova KO, Soares VC, Hoffman ES, Ono M, Khanam D, Hayday AC, Frohman LA, Koff A (May 1996). "Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1)". Cell 85 (5): 721–32. doi:10.1016/S0092-8674(00)81238-6. PMID 8646780. 
  5. ^ Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I, Loh DY, Nakayama K (May 1996). "Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors". Cell 85 (5): 707–20. doi:10.1016/S0092-8674(00)81237-4. PMID 8646779. 
  6. ^ Klopfleisch R, Gruber AD. (January 2009). "Differential expression of cell cycle regulators p21, p27 and p53 in metastasizing canine mammary adenocarcinomas versus normal mammary glands". Res Vet Sci. 87 (1): 91–6. doi:10.1016/j.rvsc.2008.12.010. PMID 19185891. 
  7. ^ Klopfleisch R, Schütze M, Gruber AD. (September 2010). "Loss of p27 expression in canine mammary tumors and their metastases". Res Vet Sci. 88 (2): 300–3. doi:10.1016/j.rvsc.2009.08.007. PMID 19748645. 
  8. ^ Klopfleisch R, von Euler H, Sarli G, Pinho SS, Gärtner F, Gruber AD. (2010). "Molecular Carcinogenesis of Canine Mammary Tumors: News From an Old Disease". Veterinary Pathology 228 (1): 98–116. doi:10.1177/0300985810390826. PMID 21149845. 
  9. ^ Klopfleisch R, Schütze M, Gruber AD. (October 2009). "Downregulation of transforming growth factor β (TGFβ) and latent TGFβ binding protein (LTBP)-4 expression in late stage canine mammary tumours". Veterinary Journal 186 (3): 379–84. doi:10.1016/j.tvjl.2009.09.014. PMID 19836277. 
  10. ^ Göpfert U, Kullmann M, Hengst L (July 2003). "Cell cycle-dependent translation of p27 involves a responsive element in its 5'-UTR that overlaps with a uORF". Hum. Mol. Genet. 12 (14): 1767–79. doi:10.1093/hmg/ddg177. PMID 12837699. 
  11. ^ a b c d e f g le Sage C, Nagel R, Agami R (November 2007). "Diverse ways to control p27Kip1 function: miRNAs come into play". Cell Cycle 6 (22): 2742–9. doi:10.4161/cc.6.22.4900. PMID 17986865. 
  12. ^ a b c d e f g h i j k l m n o p q r s t u v Chu IM, Hengst L, Slingerland JM (April 2008). "The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy". Nat. Rev. Cancer 8 (4): 253–67. doi:10.1038/nrc2347. PMID 18354415. 
  13. ^ a b c d Nakayama KI, Nakayama K (May 2006). "Ubiquitin ligases: cell-cycle control and cancer". Nat. Rev. Cancer 6 (5): 369–81. doi:10.1038/nrc1881. PMID 16633365. 
  14. ^ Kotoshiba S, Kamura T, Hara T, Ishida N, Nakayama KI (May 2005). "Molecular dissection of the interaction between p27 and Kip1 ubiquitylation-promoting complex, the ubiquitin ligase that regulates proteolysis of p27 in G1 phase". J. Biol. Chem. 280 (18): 17694–700. doi:10.1074/jbc.M500866200. PMID 15746103. 
  15. ^ a b Ishida N, Hara T, Kamura T, Yoshida M, Nakayama K, Nakayama KI (April 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. 
  16. ^ a b c d Chu I, Sun J, Arnaout A, Kahn H, Hanna W, Narod S, Sun P, Tan CK, Hengst L, Slingerland J (January 2007). "p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2". Cell 128 (2): 281–94. doi:10.1016/j.cell.2006.11.049. PMC 1961623. PMID 17254967. 
  17. ^ McAllister SS, Becker-Hapak M, Pintucci G, Pagano M, Dowdy SF (January 2003). "Novel p27(kip1) C-terminal scatter domain mediates Rac-dependent cell migration independent of cell cycle arrest functions". Mol. Cell. Biol. 23 (1): 216–28. doi:10.1128/MCB.23.1.216-228.2003. PMC 140659. PMID 12482975. 
  18. ^ Wu FY, Wang SE, Sanders ME, Shin I, Rojo F, Baselga J, Arteaga CL (February 2006). "Reduction of cytosolic p27(Kip1) inhibits cancer cell motility, survival, and tumorigenicity". Cancer Res. 66 (4): 2162–72. doi:10.1158/0008-5472.CAN-05-3304. PMID 16489017. 
  19. ^ Denicourt C, Saenz CC, Datnow B, Cui XS, Dowdy SF (October 2007). "Relocalized p27Kip1 tumor suppressor functions as a cytoplasmic metastatic oncogene in melanoma". Cancer Res. 67 (19): 9238–43. doi:10.1158/0008-5472.CAN-07-1375. PMID 17909030. 
  20. ^ Cheng M, Sexl V, Sherr CJ, Roussel MF (February 1998). "Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1)". Proc. Natl. Acad. Sci. U.S.A. 95 (3): 1091–6. doi:10.1073/pnas.95.3.1091. PMC 18683. PMID 9448290. 
  21. ^ Liu X, Sun Y, Ehrlich M, Lu T, Kloog Y, Weinberg RA, Lodish HF, Henis YI (November 2000). "Disruption of TGF-beta growth inhibition by oncogenic ras is linked to p27Kip1 mislocalization". Oncogene 19 (51): 5926–35. doi:10.1038/sj.onc.1203991. PMID 11127824. 
  22. ^ Viglietto G, Motti ML, Bruni P, Melillo RM, D'Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A, Santoro M (October 2002). "Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer". Nat. Med. 8 (10): 1136–44. doi:10.1038/nm762. PMID 12244303. 
  23. ^ Larrea MD, Hong F, Wander SA, da Silva TG, Helfman D, Lannigan D, Smith JA, Slingerland JM (June 2009). "RSK1 drives p27Kip1 phosphorylation at T198 to promote RhoA inhibition and increase cell motility". Proc. Natl. Acad. Sci. U.S.A. 106 (23): 9268–73. doi:10.1073/pnas.0805057106. PMC 2695095. PMID 19470470. 
  24. ^ a b Larrea MD, Wander SA, Slingerland JM (November 2009). "p27 as Jekyll and Hyde: regulation of cell cycle and cell motility". Cell Cycle 8 (21): 3455–61. doi:10.4161/cc.8.21.9789. PMID 19829074. 
  25. ^ a b Baldassarre G, Belletti B, Nicoloso MS, Schiappacassi M, Vecchione A, Spessotto P, Morrione A, Canzonieri V, Colombatti A (January 2005). "p27(Kip1)-stathmin interaction influences sarcoma cell migration and invasion". Cancer Cell 7 (1): 51–63. doi:10.1016/j.ccr.2004.11.025. PMID 15652749. 
  26. ^ Chappuis PO, Kapusta L, Bégin LR, Wong N, Brunet JS, Narod SA, Slingerland J, Foulkes WD (December 2000). "Germline BRCA1/2 mutations and p27(Kip1) protein levels independently predict outcome after breast cancer". J. Clin. Oncol. 18 (24): 4045–52. PMID 11118465. 
  27. ^ Chang BL, Zheng SL, Isaacs SD, Wiley KE, Turner A, Li G, Walsh PC, Meyers DA, Isaacs WB, Xu J (March 2004). "A polymorphism in the CDKN1B gene is associated with increased risk of hereditary prostate cancer". Cancer Res. 64 (6): 1997–9. doi:10.1158/0008-5472.CAN-03-2340. PMID 15026335. 
  28. ^ Masciullo V, Sgambato A, Pacilio C, Pucci B, Ferrandina G, Palazzo J, Carbone A, Cittadini A, Mancuso S, Scambia G, Giordano A (August 1999). "Frequent loss of expression of the cyclin-dependent kinase inhibitor p27 in epithelial ovarian cancer". Cancer Res. 59 (15): 3790–4. PMID 10446997. 
  29. ^ Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, Shaw P, Yeger H, Morava-Protzner I, Kapusta L, Franssen E, Pritchard KI, Slingerland JM (February 1997). "Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer". Nat. Med. 3 (2): 227–30. doi:10.1038/nm0297-227. PMID 9018244. 
  30. ^ a b Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, Jessup JM, Pagano M (February 1997). "Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas". Nat. Med. 3 (2): 231–4. doi:10.1038/nm0297-231. PMID 9018245. 
  31. ^ a b Esposito V, Baldi A, De Luca A, Groger AM, Loda M, Giordano GG, Caputi M, Baldi F, Pagano M, Giordano A (August 1997). "Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer". Cancer Res. 57 (16): 3381–5. PMID 9270000. 
  32. ^ Tsihlias J, Kapusta LR, DeBoer G, Morava-Protzner I, Zbieranowski I, Bhattacharya N, Catzavelos GC, Klotz LH, Slingerland JM (February 1998). "Loss of cyclin-dependent kinase inhibitor p27Kip1 is a novel prognostic factor in localized human prostate adenocarcinoma". Cancer Res. 58 (3): 542–8. PMID 9458103. 
  33. ^ Oshita F, Kameda Y, Nishio K, Tanaka G, Yamada K, Nomura I, Nakayama H, Noda K (2000). "Increased expression levels of cyclin-dependent kinase inhibitor p27 correlate with good responses to platinum-based chemotherapy in non-small cell lung cancer". Oncol. Rep. 7 (3): 491–5. doi:10.3892/or.7.3.491. PMID 10767357. 
  34. ^ Porter PL, Barlow WE, Yeh IT, Lin MG, Yuan XP, Donato E, Sledge GW, Shapiro CL, Ingle JN, Haskell CM, Albain KS, Roberts JM, Livingston RB, Hayes DF (December 2006). "p27(Kip1) and cyclin E expression and breast cancer survival after treatment with adjuvant chemotherapy". J. Natl. Cancer Inst. 98 (23): 1723–31. doi:10.1093/jnci/djj467. PMC 2727647. PMID 17148774. 
  35. ^ a b Blain SW, Scher HI, Cordon-Cardo C, Koff A (February 2003). "p27 as a target for cancer therapeutics". Cancer Cell 3 (2): 111–5. doi:10.1016/S1535-6108(03)00026-6. PMID 12620406. 
  36. ^ a b Fujita N, Sato S, Katayama K, Tsuruo T (2002). "Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization". J. Biol. Chem. 277 (32): 28706–13. doi:10.1074/jbc.M203668200. PMID 12042314. 
  37. ^ a b Wang W, Ungermannova D, Chen L, Liu X (2003). "A negatively charged amino acid in Skp2 is required for Skp2-Cks1 interaction and ubiquitination of p27Kip1". J. Biol. Chem. 278 (34): 32390–6. doi:10.1074/jbc.M305241200. PMID 12813041. 
  38. ^ a b Sitry D, Seeliger MA, Ko TK, Ganoth D, Breward SE, Itzhaki LS, Pagano M, Hershko A (2002). "Three different binding sites of Cks1 are required for p27-ubiquitin ligation". J. Biol. Chem. 277 (44): 42233–40. doi:10.1074/jbc.M205254200. PMID 12140288. 
  39. ^ a b Lin J, Jinno S, Okayama H (2001). "Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence". Oncogene 20 (16): 2000–9. doi:10.1038/sj.onc.1204375. PMID 11360184. 
  40. ^ Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514. 
  41. ^ Zhang Q, Wang X, Wolgemuth DJ (1999). "Developmentally regulated expression of cyclin D3 and its potential in vivo interacting proteins during murine gametogenesis". Endocrinology 140 (6): 2790–800. doi:10.1210/en.140.6.2790. PMID 10342870. 
  42. ^ a b c Connor MK, Kotchetkov R, Cariou S, Resch A, Lupetti R, Beniston RG, Melchior F, Hengst L, Slingerland JM (2003). "CRM1/Ran-mediated nuclear export of p27(Kip1) involves a nuclear export signal and links p27 export and proteolysis". Mol. Biol. Cell 14 (1): 201–13. doi:10.1091/mbc.E02-06-0319. PMC 140238. PMID 12529437. 
  43. ^ Shanahan F, Seghezzi W, Parry D, Mahony D, Lees E (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". Mol. Cell. Biol. 19 (2): 1460–9. PMC 116074. PMID 9891079. 
  44. ^ a b Porter LA, Kong-Beltran M, Donoghue DJ (2003). "Spy1 interacts with p27Kip1 to allow G1/S progression". Mol. Biol. Cell 14 (9): 3664–74. doi:10.1091/mbc.E02-12-0820. PMC 196558. PMID 12972555. 
  45. ^ Youn CK, Cho HJ, Kim SH, Kim HB, Kim MH, Chang IY, Lee JS, Chung MH, Hahm KS, You HJ (2005). "Bcl-2 expression suppresses mismatch repair activity through inhibition of E2F transcriptional activity". Nat. Cell Biol. 7 (2): 137–47. doi:10.1038/ncb1215. PMID 15619620. 
  46. ^ 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. 
  47. ^ 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. 
  48. ^ 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. 
  49. ^ 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. 
  50. ^ 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. 
  51. ^ 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. PMID 12771291. 
  • Drexler HC (2004). "The role of p27Kip1 in proteasome inhibitor induced apoptosis". Cell Cycle 2 (5): 438–41. 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. 

External links[edit]