Skp2

Summary

Gene Symbol: Skp2
Description: S-phase kinase associated protein 2
Alias: FBL1, FBXL1, FLB1, p45, S-phase kinase-associated protein 2, CDK2/cyclin A-associated protein p45, F-box/LRR-repeat protein 1, S-phase kinase-associated protein 2, E3 ubiquitin protein ligase, p45skp2
Species: human
Products:     Skp2

Top Publications

  1. Schulman B, Carrano A, Jeffrey P, Bowen Z, Kinnucan E, Finnin M, et al. Insights into SCF ubiquitin ligases from the structure of the Skp1-Skp2 complex. Nature. 2000;408:381-6 pubmed
    ..Here we describe the crystal structure of the human F-box protein Skp2 bound to Skp1...
  2. Min K, Hwang J, Lee J, Park Y, Tamura T, Yoon J. TIP120A associates with cullins and modulates ubiquitin ligase activity. J Biol Chem. 2003;278:15905-10 pubmed
    ..These results suggest that TIP120A functions as a negative regulator of SCF E3 ubiquitin ligases and may modulate other cullin ligases in a similar fashion. ..
  3. Li Q, Murphy M, Ross J, Sheehan C, Carlson J. Skp2 and p27kip1 expression in melanocytic nevi and melanoma: an inverse relationship. J Cutan Pathol. 2004;31:633-42 pubmed
    S-phase kinase associated protein-2 (Skp2) ubiquitin ligase p45(SKP2) is important in the degradation of p27kip1 (a cyclin dependent kinase inhibitor) and progression through the G1-S cell-cycle checkpoint...
  4. Abdou A, Asaad N, Abd El Wahed M, Samaka R, Allah M. The prognostic value of Skp2 expression in Egyptian diffuse large B-cell lymphoma. Appl Immunohistochem Mol Morphol. 2012;20:47-55 pubmed publisher
    ..S-phase kinase-associated protein 2 (Skp2) is a member of mammalian F-box proteins, which displays S-phase-promoting function through ubiquitin-mediated ..
  5. Nie L, Wu H, Sun X. Ubiquitination and degradation of Tal1/SCL are induced by notch signaling and depend on Skp2 and CHIP. J Biol Chem. 2008;283:684-92 pubmed
    ..Analogous to the situation for E47, Notch-induced Tal1/SCL degradation not only required Skp2, a substrate-binding subunit of SCF ubiquitin ligase complexes, but also relied on CHIP, a chaperone-binding ..
  6. Liu Y, Hedvat C, Mao S, Zhu X, Yao J, Nguyen H, et al. The ETS protein MEF is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCFSkp2. Mol Cell Biol. 2006;26:3114-23 pubmed
    ..and serine 648 at the C terminus of MEF by cdk2 and on the Skp1/Cul1/F-box (SCF) E3 ubiquitin ligase complex SCF(Skp2), which targets MEF for ubiquitination and proteolysis...
  7. Muth D, Ghazaryan S, Eckerle I, Beckett E, Pöhler C, Batzler J, et al. Transcriptional repression of SKP2 is impaired in MYCN-amplified neuroblastoma. Cancer Res. 2010;70:3791-802 pubmed publisher
    The cell cycle regulator, SKP2, is overexpressed in various cancers and plays a key role in p27 degradation, which is involved in tumor cell dedifferentiation...
  8. Li J, Wu F, Masaki T, Kubo A, Fujita J, Dixon D, et al. Correlation of Skp2 with carcinogenesis, invasion, metastasis, and prognosis in colorectal tumors. Int J Oncol. 2004;25:87-95 pubmed
    In colorectal tumors, S-phase kinase-associated protein 2 (Skp2) still has numerous important questions unanswered: its expression in adenomas, its correlation with key clinicopathological indices, its association with patient prognosis, ..
  9. Zheng W, Zheng J, Ma R, Meng F, Ni C. Relationship between levels of Skp2 and P27 in breast carcinomas and possible role of Skp2 as targeted therapy. Steroids. 2005;70:770-4 pubmed
    ..The S-phase kinase-associated protein Skp2 is required for the ubiquitin-mediated degradation of the cdk-inhibitor p27 and is a bona fide proto-oncoprotein...

More Information

Publications100

  1. Chan C, Li C, Yang W, Gao Y, Lee S, Feng Z, et al. The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. Cell. 2012;149:1098-111 pubmed publisher
    ..is also induced by activation of ErbB receptors; unexpectedly, and in contrast to IGF-1 induced activation, the Skp2 SCF complex, not TRAF6, is a critical E3 ligase for ErbB-receptor-mediated Akt ubiquitination and membrane ..
  2. Ganoth D, Bornstein G, Ko T, Larsen B, Tyers M, Pagano M, et al. The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27. Nat Cell Biol. 2001;3:321-4 pubmed
    ..its phosphorylation at Thr 187 (refs 3, 4) and subsequent recognition by S-phase kinase associated protein 2 (Skp2; refs 5-8), a member of the F-box family of proteins that associates with Skp1, Cul-1 and ROC1/Rbx1 to form an SCF ..
  3. Nie L, Xu M, Vladimirova A, Sun X. Notch-induced E2A ubiquitination and degradation are controlled by MAP kinase activities. EMBO J. 2003;22:5780-92 pubmed
    ..Expression of the intracellular domain of Notch1 (N1-IC) enhances the association of E47 with the SCF(Skp2) E3 ubiquitin ligase and ubiquitination of E47, followed by proteasome-mediated degradation...
  4. Latres E, Chiarle R, Schulman B, Pavletich N, Pellicer A, Inghirami G, et al. Role of the F-box protein Skp2 in lymphomagenesis. Proc Natl Acad Sci U S A. 2001;98:2515-20 pubmed
    The F-box protein Skp2 (S-phase kinase-associated protein 2) positively regulates the G(1)-S transition by controlling the stability of several G(1) regulators, such as the cell cycle inhibitor p27...
  5. Xu H, Liang Y, Chen Q, Wu Q, Guo Y, Shen G, et al. Correlation of Skp2 overexpression to prognosis of patients with nasopharyngeal carcinoma from South China. Chin J Cancer. 2011;30:204-12 pubmed
    S-phase kinase-associated protein 2 (Skp2), which plays a role in cell cycle regulation, is commonly overexpressed in a variety of human cancers and associated with poor prognosis...
  6. Lin Y, Yang J. Cooperation of ERK and SCFSkp2 for MKP-1 destruction provides a positive feedback regulation of proliferating signaling. J Biol Chem. 2006;281:915-26 pubmed
    ..Intriguingly, active ERK-promoted phospho-Ser(296) MKP-1 bound to SCF(Skp2) ubiquitin ligase in vivo and in vitro...
  7. Osoegawa A, Yoshino I, Tanaka S, Sugio K, Kameyama T, Yamaguchi M, et al. Regulation of p27 by S-phase kinase-associated protein 2 is associated with aggressiveness in non-small-cell lung cancer. J Clin Oncol. 2004;22:4165-73 pubmed
    The F-box protein S-phase kinase-associated protein 2 (Skp2) is one of the positive regulators of the cell cycle that promote ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27...
  8. Ji P, Jiang H, Rekhtman K, Bloom J, Ichetovkin M, Pagano M, et al. An Rb-Skp2-p27 pathway mediates acute cell cycle inhibition by Rb and is retained in a partial-penetrance Rb mutant. Mol Cell. 2004;16:47-58 pubmed
    ..Conversely, Rb knockout leads to faster p27 degradation. Rb interacts with the N terminus of Skp2, interferes with Skp2-p27 interaction, and inhibits ubiquitination of p27...
  9. Marti A, Wirbelauer C, Scheffner M, Krek W. Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation. Nat Cell Biol. 1999;1:14-9 pubmed
    ..This event is linked to a specific interaction of E2F-1 with the F-box-containing protein p45SKP2, which is the cell-cycle-regulated component of the ubiquitin-protein ligase SCFSKP2 that recognizes substrates ..
  10. Huang H, Regan K, Wang F, Wang D, Smith D, van Deursen J, et al. Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. Proc Natl Acad Sci U S A. 2005;102:1649-54 pubmed
    ..Here we demonstrate that Skp2, an oncogenic subunit of the Skp1/Cul1/F-box protein ubiquitin complex, interacts with, ubiquitinates, and promotes ..
  11. Fang F, Chien C, Li C, Shiu W, Chen C, Huang H. Effect of S-phase kinase-associated protein 2 expression on distant metastasis and survival in nasopharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys. 2009;73:202-7 pubmed publisher
    The S-phase kinase-associated protein 2 (Skp2) oncoprotein is an E3 ubiquitin ligase targeting the p27(Kip1) tumor suppressor for degradation...
  12. Wang X, Tian L, Tian J, Jiang X. Overexpression of SKP2 promotes the radiation resistance of esophageal squamous cell carcinoma. Radiat Res. 2012;177:52-8 pubmed
    b>SKP2 is the substrate recognition subunit of the SCF(SKP2) ubiquitin ligase complex...
  13. von der Lehr N, Johansson S, Larsson L. Implication of the ubiquitin/proteasome system in Myc-regulated transcription. Cell Cycle. 2003;2:403-7 pubmed
    ..We and others recently showed that the F-box protein Skp2 interacts with c-Myc and participates in its ubiquitylation and proteasomal degradation...
  14. Bhattacharya S, Garriga J, Calbo J, Yong T, Haines D, Grana X. SKP2 associates with p130 and accelerates p130 ubiquitylation and degradation in human cells. Oncogene. 2003;22:2443-51 pubmed
    ..Since the SKP1/Cul1/SKP2 E3 ubiquitin ligase complex mediates ubiquitylation of substrates previously phosphorylated by cyclin-dependent ..
  15. Lu L, Schulz H, Wolf D. The F-box protein SKP2 mediates androgen control of p27 stability in LNCaP human prostate cancer cells. BMC Cell Biol. 2002;3:22 pubmed
    ..cancer cell line LNCaP, which undergoes G1 cell cycle arrest in response to androgen, to examine the role of the SKP2 F-box protein in p27 regulation in prostate cancer...
  16. Bhatt K, Hu R, Spofford L, Aplin A. Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells. Oncogene. 2007;26:1056-66 pubmed
    ..Additionally, B-RAF and cyclin D1 control the levels of S-phase kinase-associated protein 2 (Skp2) that directs ubiquitin-mediated proteolysis of p27(Kip1)...
  17. Zhang H, Kobayashi R, Galaktionov K, Beach D. p19Skp1 and p45Skp2 are essential elements of the cyclin A-CDK2 S phase kinase. Cell. 1995;82:915-25 pubmed
    ..transformed cells, p21 disappears, and a substantial fraction of cyclin A-CDK2 complexes with p9CKS1/CKS2, p19, and p45. To investigate the significance of these rearrangements, we have isolated cDNAs encoding p19 and p45...
  18. Wu L, Grigoryan A, Li Y, Hao B, Pagano M, Cardozo T. Specific small molecule inhibitors of Skp2-mediated p27 degradation. Chem Biol. 2012;19:1515-24 pubmed publisher
    In the ubiquitin proteasome system, the E3 ligase SCF-Skp2 and its accessory protein, Cks1, promote proliferation largely by inducing the degradation of the CDK inhibitor p27...
  19. Seki R, Ohshima K, Fujisaki T, Uike N, Kawano F, Gondo H, et al. Prognostic significance of S-phase kinase-associated protein 2 and p27kip1 in patients with diffuse large B-cell lymphoma: effects of rituximab. Ann Oncol. 2010;21:833-41 pubmed publisher
    The F-box protein S-phase kinase-associated protein 2 (Skp2) positively regulates the G1-S transition by promoting degradation of the cyclin-dependent kinase inhibitor p27(kip1) (p27)...
  20. Arbini A, Greco M, Yao J, Bourne P, Marra E, Hsieh J, et al. Skp2 overexpression is associated with loss of BRCA2 protein in human prostate cancer. Am J Pathol. 2011;178:2367-76 pubmed publisher
    ..Previous in vitro experiments demonstrated that Skp2, an E3 ubiquitin ligase aberrantly overexpressed in PCa, is involved in the proteolytic degradation of BRCA2 in PCa ..
  21. Huang H, Kang H, Li C, Eng H, Chou S, Lin C, et al. Skp2 overexpression is highly representative of intrinsic biological aggressiveness and independently associated with poor prognosis in primary localized myxofibrosarcomas. Clin Cancer Res. 2006;12:487-98 pubmed
    Two SCF(Skp2) ubiquitin ligase-related proteins, Skp2 and cyclin-dependent kinase subunit 1 (Cks1), are involved in posttranscriptional degradation of p27(Kip1) tumor suppressor...
  22. Wang H, Sun D, Ji P, Mohler J, Zhu L. An AR-Skp2 pathway for proliferation of androgen-dependent prostate-cancer cells. J Cell Sci. 2008;121:2578-87 pubmed publisher
    ..Herein, we report the identification of an AR-Skp2 pathway in prostate-cancer cells that depend on the AR for proliferation; in this pathway, AR is a robust upstream ..
  23. Rose A, Wang G, Hanniford D, Monni S, Tu T, Shapiro R, et al. Clinical relevance of SKP2 alterations in metastatic melanoma. Pigment Cell Melanoma Res. 2011;24:197-206 pubmed publisher
    In this study, we investigated the mechanism(s) of altered expression of protooncogene SKP2 in metastatic melanoma and its clinical relevance in patients with metastatic melanoma...
  24. Chen G, Cheng Y, Zhang Z, Martinka M, Li G. Cytoplasmic Skp2 expression is increased in human melanoma and correlated with patient survival. PLoS ONE. 2011;6:e17578 pubmed publisher
    S-phase kinase protein 2 (Skp2), an F-box protein, targets cell cycle regulators via ubiquitin-mediated degradation. Skp2 is frequently overexpressed in a variety of cancers and associated with patient survival...
  25. Lisztwan J, Marti A, Sutterlüty H, Gstaiger M, Wirbelauer C, Krek W. Association of human CUL-1 and ubiquitin-conjugating enzyme CDC34 with the F-box protein p45(SKP2): evidence for evolutionary conservation in the subunit composition of the CDC34-SCF pathway. EMBO J. 1998;17:368-83 pubmed
    In normal and transformed cells, the F-box protein p45(SKP2) is required for S phase and forms stable complexes with p19(SKP1) and cyclin A-cyclin-dependent kinase (CDK)2...
  26. Duda D, Borg L, Scott D, Hunt H, Hammel M, Schulman B. Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation. Cell. 2008;134:995-1006 pubmed publisher
    ..Thus, our results point to a conformational control of CRL activity, with ligation of NEDD8 shifting equilibria to disfavor inactive CAND1-bound closed architectures, and favor dynamic, open forms that promote polyubiquitination. ..
  27. Bashir T, Pagan J, Busino L, Pagano M. Phosphorylation of Ser72 is dispensable for Skp2 assembly into an active SCF ubiquitin ligase and its subcellular localization. Cell Cycle. 2010;9:971-4 pubmed
    F-box proteins are the substrate recognition subunits of SCF (Skp1, Cul1, F-box protein) ubiquitin ligase complexes. Skp2 is a nuclear F-box protein that targets the CDK inhibitor p27 for ubiquitin- and proteasome-dependent degradation...
  28. Rodier G, Makris C, Coulombe P, Scime A, Nakayama K, Nakayama K, et al. p107 inhibits G1 to S phase progression by down-regulating expression of the F-box protein Skp2. J Cell Biol. 2005;168:55-66 pubmed
    ..Instead, we observed a marked decrease in the abundance of the F-box receptor Skp2 in p107-overexpressing cells. Reciprocally, Skp2 accumulates to higher levels in p107-/- embryonic fibroblasts...
  29. Meng J, Ding Y, Shen A, Yan M, He F, Ji H, et al. Overexpression of PPAR? can down-regulate Skp2 expression in MDA-MB-231 breast tumor cells. Mol Cell Biochem. 2010;345:171-80 pubmed publisher
    b>Skp2 is frequent amplified and overexpressed in breast cancer, making it a potential molecular target for cancer therapy...
  30. Ji P, Goldin L, Ren H, Sun D, Guardavaccaro D, Pagano M, et al. Skp2 contains a novel cyclin A binding domain that directly protects cyclin A from inhibition by p27Kip1. J Biol Chem. 2006;281:24058-69 pubmed
    b>Skp2 is well known as the F-box protein of the SCF(Skp2) x Roc1 complex targeting p27 for ubiquitylation...
  31. Chen G, Wang Y, Garate M, Zhou J, Li G. The tumor suppressor ING3 is degraded by SCF(Skp2)-mediated ubiquitin-proteasome system. Oncogene. 2010;29:1498-508 pubmed publisher
    ..Knockdown of F-box protein S-phase kinase-associated protein 2 (Skp2) reduces the ubiquitination of ING3 and significantly stabilizes ING3 in melanoma cells...
  32. Zhu C, Blackhall F, Pintilie M, Iyengar P, Liu N, Ho J, et al. Skp2 gene copy number aberrations are common in non-small cell lung carcinoma, and its overexpression in tumors with ras mutation is a poor prognostic marker. Clin Cancer Res. 2004;10:1984-91 pubmed
    b>Skp2 plays a critical role in cell cycle progression, especially at the G(1)-S transition, putatively through its control of several cell cycle regulator proteins...
  33. Chan C, Morrow J, Li C, Gao Y, Jin G, Moten A, et al. Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression. Cell. 2013;154:556-68 pubmed publisher
    b>Skp2 E3 ligase is overexpressed in numerous human cancers and plays a critical role in cell-cycle progression, senescence, metabolism, cancer progression, and metastasis...
  34. Carrano A, Eytan E, Hershko A, Pagano M. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol. 1999;1:193-9 pubmed
    ..Here we show that the F-box protein SKP2 specifically recognizes p27 in a phosphorylation-dependent manner that is characteristic of an F-box-protein-..
  35. Nguyen P, Lin D, Lei J, Fiorentino M, Mueller E, Weinstein M, et al. The impact of Skp2 overexpression on recurrence-free survival following radical prostatectomy. Urol Oncol. 2011;29:302-8 pubmed publisher
    In several human cancers, overexpression of Skp2 (S-phase kinase associated protein 2), which targets p27 for degradation, portends a poorer prognosis...
  36. Ma X, Liu Y, Guo J, Liu J, Zuo L. Relation of overexpression of S phase kinase-associated protein 2 with reduced expression of p27 and PTEN in human gastric carcinoma. World J Gastroenterol. 2005;11:6716-21 pubmed
    To investigate the significance of S phase kinase-associated protein 2 (Skp2) expression in human gastric carcinoma and the relation between expressions of Skp2, p27 and PTEN...
  37. Min Y, Cheong J, Lee M, Kim J, Lee S, Hahn J, et al. Elevated S-phase kinase-associated protein 2 protein expression in acute myelogenous leukemia: its association with constitutive phosphorylation of phosphatase and tensin homologue protein and poor prognosis. Clin Cancer Res. 2004;10:5123-30 pubmed
    The F-box protein S-phase kinase-associated protein 2 (Skp2) positively regulates the G(1)-S phase transition by controlling the stability of several G(1) regulators, such as p27Kip1...
  38. Liu H, Cheng E, Hsieh J. Bimodal degradation of MLL by SCFSkp2 and APCCdc20 assures cell cycle execution: a critical regulatory circuit lost in leukemogenic MLL fusions. Genes Dev. 2007;21:2385-98 pubmed
    ..Specifically, SCF(Skp2) and APC(Cdc20) mark MLL for degradation at S phase and late M phase, respectively...
  39. Yung Y, Walker J, Roberts J, Assoian R. A Skp2 autoinduction loop and restriction point control. J Cell Biol. 2007;178:741-7 pubmed
    We describe a self-amplifying feedback loop that autoinduces Skp2 during G1 phase progression...
  40. Chua Y, Boh B, Ponyeam W, Hagen T. Regulation of cullin RING E3 ubiquitin ligases by CAND1 in vivo. PLoS ONE. 2011;6:e16071 pubmed publisher
    ..In conclusion, our study suggests that CAND1 does not function by sequestering cullins in vivo to prevent substrate receptor autoubiquitination and is likely to regulate cullin RING ligase activity via alternative mechanisms. ..
  41. Yokoi S, Yasui K, Mori M, Iizasa T, Fujisawa T, Inazawa J. Amplification and overexpression of SKP2 are associated with metastasis of non-small-cell lung cancers to lymph nodes. Am J Pathol. 2004;165:175-80 pubmed
    b>SKP2, an F-box protein constituting the substrate recognition subunit of the SCF(SKP2) ubiquitin ligase complex, is implicated in ubiquitin-mediated degradation of the cyclin-dependent kinase inhibitor p27(KIP1)...
  42. Lin H, Wang G, Chen Z, Teruya Feldstein J, Liu Y, Chan C, et al. Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB. Nat Cell Biol. 2009;11:420-32 pubmed publisher
    b>Skp2 is an F-box protein that forms the SCF complex with Skp1 and Cullin-1 to constitute an E3 ligase for ubiquitylation...
  43. Inuzuka H, Gao D, Finley L, Yang W, Wan L, Fukushima H, et al. Acetylation-dependent regulation of Skp2 function. Cell. 2012;150:179-93 pubmed publisher
    Aberrant Skp2 signaling has been implicated as a driving event in tumorigenesis. Although the underlying molecular mechanisms remain elusive, cytoplasmic Skp2 correlates with more aggressive forms of breast and prostate cancers...
  44. Kamura T, Hara T, Kotoshiba S, Yada M, Ishida N, Imaki H, et al. Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation. Proc Natl Acad Sci U S A. 2003;100:10231-6 pubmed
    ..The elimination of p57Kip2 was impaired in Skp2-/- cells, resulting in abnormal accumulation of the protein...
  45. Cen B, Mahajan S, Zemskova M, Beharry Z, Lin Y, Cramer S, et al. Regulation of Skp2 levels by the Pim-1 protein kinase. J Biol Chem. 2010;285:29128-37 pubmed publisher
    ..To understand how Pim-1 is capable of regulating p27 protein levels, we focused our attention on the SCF(Skp2) ubiquitin ligase complex that controls the rate of degradation of this protein...
  46. Wu J, Zhang X, Zhang L, Wu C, Rezaeian A, Chan C, et al. Skp2 E3 ligase integrates ATM activation and homologous recombination repair by ubiquitinating NBS1. Mol Cell. 2012;46:351-61 pubmed publisher
    ..Here we show that Skp2 E3 ligase is a key component for the MRN complex-mediated ATM activation in response to DSBs...
  47. Watanabe N, Arai H, Nishihara Y, Taniguchi M, Watanabe N, Hunter T, et al. M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP. Proc Natl Acad Sci U S A. 2004;101:4419-24 pubmed
    ..These results also establish the existence of a feedback loop between Cdc2 and Wee1A in somatic cells that depends on ubiquitination and protein degradation and ensures the rapid activation of Cdc2 when cells are ready to divide. ..
  48. Carrano A, Pagano M. Role of the F-box protein Skp2 in adhesion-dependent cell cycle progression. J Cell Biol. 2001;153:1381-90 pubmed
    ..We have reported previously that the degradation of p27 requires its phosphorylation on Thr-187 and is mediated by Skp2, an F-box protein that associates with Skp1, Cul1, and Roc1/Rbx1 to form the SCF(Skp2) ubiquitin ligase complex...
  49. van Duijn P, Trapman J. PI3K/Akt signaling regulates p27(kip1) expression via Skp2 in PC3 and DU145 prostate cancer cells, but is not a major factor in p27(kip1) regulation in LNCaP and PC346 cells. Prostate. 2006;66:749-60 pubmed
    ..As shown in LNCaP cells, p27(kip1) expression inversely correlated with Skp2 expression, but Skp2 was not regulated by Akt...
  50. Hu R, Aplin A. Skp2 regulates G2/M progression in a p53-dependent manner. Mol Biol Cell. 2008;19:4602-10 pubmed publisher
    ..S phase kinase-associated protein 2 (Skp2) is the F-box component of an E3 ubiquitin ligase complex that targets p27(Kip1) and cyclin E1 to the proteasome...
  51. Wei W, Ayad N, Wan Y, Zhang G, Kirschner M, Kaelin W. Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature. 2004;428:194-8 pubmed
    ..The major target of the Skp1/Cul1/Skp2 (SCF(SKP2)) complex is thought to be the Cdk inhibitor p27 during S phase, whereas the principal targets for the ..
  52. Nagahama H, Minamishima Y, Matsumoto M, Nakamichi I, Kitagawa K, Shirane M, et al. Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication. EMBO J. 2000;19:2069-81 pubmed
    ..Mice lacking Skp2, an F-box protein and substrate recognition component of an Skp1-Cullin-F-box protein (SCF) ubiquitin ligase, were ..
  53. Huang H, Zhao W, Yang D. Stat3 induces oncogenic Skp2 expression in human cervical carcinoma cells. Biochem Biophys Res Commun. 2012;418:186-90 pubmed publisher
    Dysregulated Skp2 function promotes cell proliferation, which is consistent with observations of Skp2 over-expression in many types of human cancers, including cervical carcinoma (CC)...
  54. Kitagawa M, Lee S, McCormick F. Skp2 suppresses p53-dependent apoptosis by inhibiting p300. Mol Cell. 2008;29:217-31 pubmed publisher
    The F box protein Skp2 is oncogenic, and its frequent amplification and overexpression correlate with the grade of malignancy of certain tumors. Conversely, depletion of Skp2 decreases cell growth and increases apoptosis...
  55. Zheng J, Yang X, Harrell J, Ryzhikov S, Shim E, Lykke Andersen K, et al. CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex. Mol Cell. 2002;10:1519-26 pubmed
    ..We found the majority of CUL1 is in a complex with CAND1 and ROC1 independent of SKP1 and F box protein SKP2. Both in vivo and in vitro, CAND1 prevents the binding of SKP1 and SKP2 to CUL1 while dissociation of CAND1 from ..
  56. Spruck C, Strohmaier H, Watson M, Smith A, Ryan A, Krek T, et al. A CDK-independent function of mammalian Cks1: targeting of SCF(Skp2) to the CDK inhibitor p27Kip1. Mol Cell. 2001;7:639-50 pubmed
    ..the ubiquitin-mediated proteolysis of the CDK-bound substrate p27Kip1 by the protein ubiquitin ligase (E3) SCF(Skp2)...
  57. Gao D, Inuzuka H, Tseng A, Chin R, Toker A, Wei W. Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1-mediated Skp2 destruction. Nat Cell Biol. 2009;11:397-408 pubmed publisher
    Deregulated Skp2 function promotes cell transformation, and this is consistent with observations of Skp2 overexpression in many human cancers. However, the mechanisms underlying elevated Skp2 expression are still unknown...
  58. Liang M, Liang Y, Wrighton K, Ungermannova D, Wang X, Brunicardi F, et al. Ubiquitination and proteolysis of cancer-derived Smad4 mutants by SCFSkp2. Mol Cell Biol. 2004;24:7524-37 pubmed
    ..We found that Skp2, the F-box component of SCFSkp2, physically interacted with Smad4 at the physiological levels...
  59. Yu Z, Gervais J, Zhang H. Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21(CIP1/WAF1) and cyclin D proteins. Proc Natl Acad Sci U S A. 1998;95:11324-9 pubmed
    ..transformed cells, the cyclin A/CDK2 complex that contains S-phase kinase associated proteins 1 and 2 (SKP1 and SKP2) is highly induced...
  60. Michel J, Xiong Y. Human CUL-1, but not other cullin family members, selectively interacts with SKP1 to form a complex with SKP2 and cyclin A. Cell Growth Differ. 1998;9:435-49 pubmed
    ..NH2-terminal domains of both proteins, and the association appears to be required for the interaction of CUL1 with SKP2, an essential element of the S-phase cyclin A-CDK2 kinase...
  61. Chew E, Poobalasingam T, Hawkey C, Hagen T. Characterization of cullin-based E3 ubiquitin ligases in intact mammalian cells--evidence for cullin dimerization. Cell Signal. 2007;19:1071-80 pubmed
    ..Using this cell line, we demonstrate that the substrate recognition subunit Skp2 and the adaptor protein Skp1 are subject to Ubc12-dependent autoubiquitination and degradation...
  62. Yang G, Ayala G, De Marzo A, Tian W, Frolov A, Wheeler T, et al. Elevated Skp2 protein expression in human prostate cancer: association with loss of the cyclin-dependent kinase inhibitor p27 and PTEN and with reduced recurrence-free survival. Clin Cancer Res. 2002;8:3419-26 pubmed
    The F-box protein Skp2 (Fbl1) is a positive regulator of G1-S transition and promotes ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27...
  63. Bretones G, Acosta J, Caraballo J, Ferrandiz N, Gomez Casares M, Albajar M, et al. SKP2 oncogene is a direct MYC target gene and MYC down-regulates p27(KIP1) through SKP2 in human leukemia cells. J Biol Chem. 2011;286:9815-25 pubmed publisher
    b>SKP2 is the ubiquitin ligase subunit that targets p27(KIP1) (p27) for degradation...
  64. Tedesco D, Lukas J, Reed S. The pRb-related protein p130 is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCF(Skp2). Genes Dev. 2002;16:2946-57 pubmed
    ..The activity of the ubiquitin ligase complex Skp1-Cul1/Cdc53-F-box protein Skp2 (SCF(Skp2)) and the proteasome were necessary for p130 degradation...
  65. Traub F, Mengel M, Lück H, Kreipe H, von Wasielewski R. Prognostic impact of Skp2 and p27 in human breast cancer. Breast Cancer Res Treat. 2006;99:185-91 pubmed
    ..The F-box protein Skp2 is a regulator of G1-S transition and promotes specifically the ubiquitin-mediated proteolysis of p27 via the ..
  66. Chew E, Hagen T. Substrate-mediated regulation of cullin neddylation. J Biol Chem. 2007;282:17032-40 pubmed
    ..These findings suggest a mechanism through which availability of substrate recognition subunits and substrates can regulate the ubiquitin ligase activity. ..
  67. Sonoda H, Inoue H, Ogawa K, Utsunomiya T, Masuda T, Mori M. Significance of skp2 expression in primary breast cancer. Clin Cancer Res. 2006;12:1215-20 pubmed
    ..the p27 expression level to be an independent prognostic factor, and a high S-phase kinase-associated protein 2 (Skp2) expression level was significantly correlated with a poor prognosis in patients with gastric cancer...
  68. Liu S, Yamauchi H. p27-Associated G1 arrest induced by hinokitiol in human malignant melanoma cells is mediated via down-regulation of pRb, Skp2 ubiquitin ligase, and impairment of Cdk2 function. Cancer Lett. 2009;286:240-9 pubmed publisher
    ..increased the stability of the p27 protein by inhibiting p27 phosphorylation at Thr(187) and by down-regulating Skp2 expression...
  69. Salon C, Merdzhanova G, Brambilla C, Brambilla E, Gazzeri S, Eymin B. E2F-1, Skp2 and cyclin E oncoproteins are upregulated and directly correlated in high-grade neuroendocrine lung tumors. Oncogene. 2007;26:6927-36 pubmed
    ..linking the status of E2F-1 and a mediator of its proteasomal degradation, the S-phase kinase-associated protein 2 (Skp2) F-box protein...
  70. Roe J, Kim H, Hwang I, Cho E, Youn H. von Hippel-Lindau protein promotes Skp2 destabilization on DNA damage. Oncogene. 2011;30:3127-38 pubmed publisher
    ..Here, we show that pVHL destabilizes the F-box protein Skp2, a chief component of Skp, Cullin, F-box-containing complex that promotes DNA synthesis in the S phase...
  71. Binné U, Classon M, Dick F, Wei W, Rape M, Kaelin W, et al. Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit. Nat Cell Biol. 2007;9:225-32 pubmed
    ..that contribute to cell-cycle control--for example, during pRB-mediated cell-cycle arrest pRB associates with Skp2, the F-box protein of the Skp1-Cullin-F-box protein (SCF) E3 ubiquitin ligase complex, and promotes the stability ..
  72. Bashir T, Dorrello N, Amador V, Guardavaccaro D, Pagano M. Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. Nature. 2004;428:190-3 pubmed
    b>Skp2 and its cofactor Cks1 are the substrate-targeting subunits of the SCF(Skp2-Cks1) (Skp1/Cul1/F-box protein) ubiquitin ligase complex that regulates entry into S phase by inducing the degradation of the cyclin-dependent kinase ..
  73. Davidovich S, Ben Izhak O, Shapira M, Futerman B, Hershko D. Over-expression of Skp2 is associated with resistance to preoperative doxorubicin-based chemotherapy in primary breast cancer. Breast Cancer Res. 2008;10:R63 pubmed publisher
    ..Over-expression of the ubiquitin ligase Skp2 results in loss of the cell cycle inhibitor p27Kip1 and is associated with poor prognosis in early breast cancer...
  74. Lyapina S, Cope G, Serino G, Tsuge T, Zhou C, Wolf D, et al. Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalosome. Science. 2001;292:1382-5 pubmed
  75. Bornstein G, Ganoth D, Hershko A. Regulation of neddylation and deneddylation of cullin1 in SCFSkp2 ubiquitin ligase by F-box protein and substrate. Proc Natl Acad Sci U S A. 2006;103:11515-20 pubmed
    ..We examined this problem for the case of SCF(Skp2), a cullin1 (Cul1)-containing ubiquitin ligase complex that contains the S phase-associated protein Skp2 as the ..
  76. Huang Y, Hung W. 1,25-dihydroxyvitamin D3 transcriptionally represses p45Skp2 expression via the Sp1 sites in human prostate cancer cells. J Cell Physiol. 2006;209:363-9 pubmed
    ..1,25-dihydroxyvitamin D3 inhibits the expression of p45Skp2, the F-box protein which is implicated in p27Kip1 degradation, to reduce turnover of p27Kip1 protein...
  77. Zheng N, Schulman B, Song L, Miller J, Jeffrey P, Wang P, et al. Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature. 2002;416:703-9 pubmed
  78. Boutonnet C, Tanguay P, Julien C, Rodier G, Coulombe P, Meloche S. Phosphorylation of Ser72 does not regulate the ubiquitin ligase activity and subcellular localization of Skp2. Cell Cycle. 2010;9:975-9 pubmed
    b>Skp2 is the substrate binding subunit of the SCF(Skp2) ubiquitin ligase, which plays a key role in the regulation of cell cycle progression...
  79. Lim M, Adamson A, Lin Z, Perez Ordonez B, Jordan R, Tripp S, et al. Expression of Skp2, a p27(Kip1) ubiquitin ligase, in malignant lymphoma: correlation with p27(Kip1) and proliferation index. Blood. 2002;100:2950-6 pubmed
    Reduced levels of p27(Kip1) are frequent in human cancers and have been associated with poor prognosis. Skp2, a component of the Skp1-Cul1-F-box protein (SCF) ubiquitin ligase complex, has been implicated in p27(Kip1) degradation...
  80. Jiang H, Chang F, Ross A, Lee J, Nakayama K, Nakayama K, et al. Ubiquitylation of RAG-2 by Skp2-SCF links destruction of the V(D)J recombinase to the cell cycle. Mol Cell. 2005;18:699-709 pubmed
    ..Remarkably, the Skp2-SCF ubiquitin ligase, which plays a central role in cell cycle regulation through the destruction of p27, mediates ..
  81. Tang Y, Simoneau A, Liao W, Yi G, Hope C, Liu F, et al. WIF1, a Wnt pathway inhibitor, regulates SKP2 and c-myc expression leading to G1 arrest and growth inhibition of human invasive urinary bladder cancer cells. Mol Cancer Ther. 2009;8:458-68 pubmed publisher
    ..The G(1) arrest induced by WIF1 is associated with down-regulation of SKP2 and c-myc and up-regulation of p21/WAF1 and p27/Kip1...
  82. Kullmann M, Grubbauer C, Goetsch K, Jakel H, Podmirseg S, Trockenbacher A, et al. The p27-Skp2 axis mediates glucocorticoid-induced cell cycle arrest in T-lymphoma cells. Cell Cycle. 2013;12:2625-35 pubmed publisher
    ..RNAi-mediated knockdown of p27 as well as overexpression of its negative regulator Skp2 revealed the critical function of p27 in the Dex-induced G 1 arrest of CEM cells...
  83. Wang X, Wu Y, Ye B, Lin D, Feng Y, Zhang Z, et al. Suppression of anoikis by SKP2 amplification and overexpression promotes metastasis of esophageal squamous cell carcinoma. Mol Cancer Res. 2009;7:12-22 pubmed publisher
    The gene of SKP2, located on chromosome 5p13, plays a critical role in cell cycle progression, especially at the G(1)-S transition, putatively through its control of several cell cycle regulator proteins including p27(kip1), p21(cip1), ..
  84. Chuu C, Kokontis J, Hiipakka R, Fukuchi J, Lin H, Lin C, et al. Androgen suppresses proliferation of castration-resistant LNCaP 104-R2 prostate cancer cells through androgen receptor, Skp2, and c-Myc. Cancer Sci. 2011;102:2022-8 pubmed publisher
    ..of 104-R2 by inducing G(1) cell cycle arrest through reduction of S-phase kinase-associated protein 2 (Skp2) and c-Myc, and induction of p27(Kip1)...
  85. Huang Y, Tong S, Tai A, Hussain M, Lok A. Hepatitis B virus core promoter mutations contribute to hepatocarcinogenesis by deregulating SKP2 and its target, p21. Gastroenterology. 2011;141:1412-21, 1421.e1-5 pubmed publisher
    ..The combo mutant increased expression of S-phase kinase-associated protein 2 (SKP2) in PHHs and Huh7 cells. Silencing of SKP2 abrogated the effects of CP mutations on p21 expression...
  86. Rodier G, Coulombe P, Tanguay P, Boutonnet C, Meloche S. Phosphorylation of Skp2 regulated by CDK2 and Cdc14B protects it from degradation by APC(Cdh1) in G1 phase. EMBO J. 2008;27:679-91 pubmed publisher
    The p27(Kip1) ubiquitin ligase receptor Skp2 is often overexpressed in human tumours and displays oncogenic properties. The activity of SCF(Skp2) is regulated by the APC(Cdh1), which targets Skp2 for degradation...
  87. Hao B, Zheng N, Schulman B, Wu G, Miller J, Pagano M, et al. Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase. Mol Cell. 2005;20:9-19 pubmed
    ..Proteolysis of p27(Kip1) is triggered by Thr187 phosphorylation, which leads to the binding of the SCF(Skp2) (Skp1-Cul1-Rbx1-Skp2) ubiquitin ligase complex...
  88. Yeh K, Kondo T, Zheng J, Tsvetkov L, Blair J, Zhang H. The F-box protein SKP2 binds to the phosphorylated threonine 380 in cyclin E and regulates ubiquitin-dependent degradation of cyclin E. Biochem Biophys Res Commun. 2001;281:884-90 pubmed
    ..We report that SKP2, an F-box protein and a substrate-targeting component of the SCF(SKP2) ubiquitin E3 ligase complex, mediates cyclin ..
  89. von der Lehr N, Johansson S, Wu S, Bahram F, Castell A, Cetinkaya C, et al. The F-box protein Skp2 participates in c-Myc proteosomal degradation and acts as a cofactor for c-Myc-regulated transcription. Mol Cell. 2003;11:1189-200 pubmed
    ..The proteins involved in this process are still unknown. We have found that Skp2 interacts with c-Myc and participates in its ubiquitylation and degradation...
  90. Jonason J, Gavrilova N, Wu M, Zhang H, Sun H. Regulation of SCF(SKP2) ubiquitin E3 ligase assembly and p27(KIP1) proteolysis by the PTEN pathway and cyclin D1. Cell Cycle. 2007;6:951-61 pubmed
    ..Silencing of the cyclin D1 gene or inhibition of the PI 3-kinase pathway prevents formation of the SCF(SKP2) complex, with a simultaneous increase in CUL1 binding to CAND1...
  91. Woenckhaus C, Maile S, Uffmann S, Bansemir M, Dittberner T, Poetsch M, et al. Expression of Skp2 and p27KIP1 in naevi and malignant melanoma of the skin and its relation to clinical outcome. Histol Histopathol. 2005;20:501-8 pubmed publisher
    b>Skp2 (S-phase kinase associated protein 2) controls progression from G- to S-phase by promoting the proteolysis of the cyclin dependent kinase inhibitor p27KIP1...