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Gene Review

SKP1  -  S-phase kinase-associated protein 1

Homo sapiens

Synonyms: Cyclin-A/CDK2-associated protein p19, EMC19, MGC34403, OCP-2, OCP-II, ...
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Disease relevance of SKP1A


Psychiatry related information on SKP1A

  • It was specific for the critical period as we did not observe any significant regulation of SKP1 mRNA by light in adult dark-reared rat brain [6].

High impact information on SKP1A

  • Using deletion analysis, we found that CUL7 uses its central region to interact with the Skp1-Fbx29 heterodimer [7].
  • At one end, a Cand1 beta hairpin protrusion partially occupies the adaptor binding site on Cul1, inhibiting its interactions with the Skp1 adaptor and the substrate-recruiting F box protein subunits [8].
  • Structure of a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase [9].
  • Neddylation of CUL1 or the presence of SKP1 and ATP causes CAND1 dissociation [10].
  • Two principal subtypes of modular ubiquitin ligase, the anaphase-promoting complex or cyclosome (APC/C) and the Skp1/Cullin-1/F-box protein complex, have emerged as essential regulators of key events in the cell cycle [11].

Biological context of SKP1A

  • Overexpression of Skp2, but not Skp1, in mammalian cells causes a G1/S cell cycle arrest [12].
  • Skp1 is also involved in diverse biological processes like degradation of key cell cycle regulators, glucose sensing, and kinetochore function [13].
  • SCF (Skp1/Cullin/F-box protein) complexes and anaphase-promoting complexes (APC) represent two major classes of ubiquitin ligases whose activities are thought to regulate primarily the G1/S and metaphase/anaphase cell-cycle transitions, respectively [14].
  • Both T-cell depletion and the neoplastic phenotype of Cul1-N252 Tg mice are largely rescued in Cul1-N252, Skp1 double-Tg mice, indicating that the effects of Cul1-N252 are due to a sequestration of the endogenous Skp1 [15].
  • Whereas only one functional Skp1 gene is present in the human genome, the genome of Caenorhabditis elegans has now been shown to contain at least 21 Skp1-related (skr) genes [16].

Anatomical context of SKP1A

  • SCF complexes (formed by Skp1, cullin, and one of many Fbps) act as protein-ubiquitin ligases that control the G(1)/S transition of the eukaryotic cell cycle [17].
  • Here we show that in primary human T lymphocytes, the SCF(skp2) core components Roc1, Cul1 and Skp1 are constitutively expressed, and their levels remain unchanged upon TCR/CD3-plus-CD28 costimulation [18].
  • One major finding in the present study is the particular decreased expression of SKP1A, a member of the SCF (E3) ligase complex specifically in the substantia nigra (SN) of sporadic parkinsonian patients, which may lead to a wide impairment in the function of an entire repertoire of proteins subjected to regulatory ubiquitination [19].
  • We found that the supplementation of Skp2-Skp1 and substrate (along with further components necessary for substrate presentation to the ubiquitin ligase) to extracts of HeLa cells synergistically increased levels of neddylated Cul1 [20].
  • The Skp1 and Cullin components have been detected on mammalian centrosomes, and shown to be essential for centrosome duplication and separation in Xenopus [13] [21].

Associations of SKP1A with chemical compounds

  • The immunogenicity and tolerogenicity of 2,4-dinitrophenyl (DNP) conjugates of levan, type 3 pneumococcal polysaccharide (SIII), dextran B512 and dextran B 1299 with different levels of substitution were assessed in vivo [22].
  • These samples were applied to each type SIII Chromarod by a single injection and developed with pure methanol or a methanol-chloroform-ammonium hydroxide (35:55:10, v/v/v) solvent system [23].
  • A special class of glycosylation occurs on a proline residue of the cytoplasmic/nuclear protein Skp1 in the social amoeba Dictyostelium [24].
  • Human skin-derived precursor cells (hSKP) were isolated and induced into an osteoblastic lineage using osteogenic induction medium (alpha-MEM plus 10% fetal bovine serum supplemented with ascorbic acid, beta-glycerophosphate and dexamethasone) [25].
  • The Skp1 GlcNAc is extended by a bifunctional diglycosyltransferase that sequentially and apparently processively adds beta1,3Gal and alpha1,2Fuc [26].

Physical interactions of SKP1A

  • We show that Skp1 can bind to Skp2 in vitro using recombinant proteins, and in vivo using the yeast two-hybrid system [13].
  • VHL forms a multimeric complex with two subunits (B and C) of the SIII (elongin) transcriptional elongation complex and CUL2, a member of the cullin family [27].
  • We found that p130 interacts with SKP1, Cul-1 and SKP2 in human 293 cells [28].
  • Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo [29].

Enzymatic interactions of SKP1A

  • Here we report that beta-TrCP is the F-box protein that targets phosphorylated Cdc25A for degradation by the Skp1/Cul1/F-box protein complex [30].

Co-localisations of SKP1A


Regulatory relationships of SKP1A

  • The F-box protein SKP2 promotes the G1-S transition by targeting key regulators for proteasomal degradation via its capacity to function as the specificity factor for the SKP1 Cullin F-box SCF(SKP2) ubiquitin ligase [32].

Other interactions of SKP1A

  • Skp1, together with F-box proteins like Skp2, are part of ubiquitin-ligase E3 complexes that target many cell cycle regulators for ubiquitination-mediated proteolysis [12].
  • These results suggest a novel, SKP1-independent mechanism for targeting E2F1 ubiquitination [33].
  • Identification of Elongin C and Skp1 sequences that determine Cullin selection [34].
  • Elongin C and Cul2, based on their homology with Skp1 and Cdc53, respectively, are suspected of targeting certain proteins for covalent modification with ubiquitin and hence for degradation [35].
  • An E3 ubiquitin ligase complex ROC1-SCF(Fbw1a) consisting of ROC1, Skp1, Cullin1, and Fbw1a (also termed betaTrCP1) induces ubiquitination of Smad3 [36].

Analytical, diagnostic and therapeutic context of SKP1A

  • In order to assess the binding properties of ts Skp1, 12 F-box proteins and Pcu1 were epitope-tagged, and co-immunoprecipitation performed [37].
  • In order to establish the role of Skp1, a temperature sensitive (ts) screen was carried out using mutagenic PCR (polymerase chain reaction) and 9 independent ts mutants were isolated [37].
  • The distribution of organ of Corti protein II (OCP-II) was assessed in the developing and mature gerbil cochlea by light and electron microscopic immunohistochemistry [38].
  • Our yeast two-hybrid assays mapped the binding interfaces to the central stalk region of CENP-E (955-1571 aa) and the C-terminal 33 amino acids of Skp1, respectively [39].
  • There was no statistically significant difference in overall survival for patients with stages SI, SII, and SIII, but the disease-free survival at 5 years by stages was found to be significant with rates of 100%, 67.6%, and 22.6% [40].


  1. Gene Expression Profiling of Sporadic Parkinson's Disease Substantia Nigra Pars Compacta Reveals Impairment of Ubiquitin-Proteasome Subunits, SKP1A, Aldehyde Dehydrogenase, and Chaperone HSC-70. Mandel, S., Grunblatt, E., Riederer, P., Amariglio, N., Jacob-Hirsch, J., Rechavi, G., Youdim, M.B. Ann. N. Y. Acad. Sci. (2005) [Pubmed]
  2. OCP2 exists as a dimer in the organ of Corti. Henzl, M.T., Thalmann, I., Thalmann, R. Hear. Res. (1998) [Pubmed]
  3. Activation and function of cyclin T-Cdk9 (positive transcription elongation factor-b) in cardiac muscle-cell hypertrophy. Sano, M., Abdellatif, M., Oh, H., Xie, M., Bagella, L., Giordano, A., Michael, L.H., DeMayo, F.J., Schneider, M.D. Nat. Med. (2002) [Pubmed]
  4. Host-cell positive transcription elongation factor b kinase activity is essential and limiting for HIV type 1 replication. Flores, O., Lee, G., Kessler, J., Miller, M., Schlief, W., Tomassini, J., Hazuda, D. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  5. Nuclear/cytoplasmic localization of the von Hippel-Lindau tumor suppressor gene product is determined by cell density. Lee, S., Chen, D.Y., Humphrey, J.S., Gnarra, J.R., Linehan, W.M., Klausner, R.D. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  6. The cell cycle gene SKP1 is regulated by light in postnatal rat brain. Uro-Coste, E., Perret, E., Fonta, C., Mathieu, M., Delisle, M.B., Caput, D., Imbert, M. Brain Res. Mol. Brain Res. (1998) [Pubmed]
  7. Identification of mutations in CUL7 in 3-M syndrome. Huber, C., Dias-Santagata, D., Glaser, A., O'Sullivan, J., Brauner, R., Wu, K., Xu, X., Pearce, K., Wang, R., Uzielli, M.L., Dagoneau, N., Chemaitilly, W., Superti-Furga, A., Dos Santos, H., Mégarbané, A., Morin, G., Gillessen-Kaesbach, G., Hennekam, R., Van der Burgt, I., Black, G.C., Clayton, P.E., Read, A., Le Merrer, M., Scambler, P.J., Munnich, A., Pan, Z.Q., Winter, R., Cormier-Daire, V. Nat. Genet. (2005) [Pubmed]
  8. Structure of the Cand1-Cul1-Roc1 complex reveals regulatory mechanisms for the assembly of the multisubunit cullin-dependent ubiquitin ligases. Goldenberg, S.J., Cascio, T.C., Shumway, S.D., Garbutt, K.C., Liu, J., Xiong, Y., Zheng, N. Cell (2004) [Pubmed]
  9. Structure of a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase. Wu, G., Xu, G., Schulman, B.A., Jeffrey, P.D., Harper, J.W., Pavletich, N.P. Mol. Cell (2003) [Pubmed]
  10. CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex. Zheng, J., Yang, X., Harrell, J.M., Ryzhikov, S., Shim, E.H., Lykke-Andersen, K., Wei, N., Sun, H., Kobayashi, R., Zhang, H. Mol. Cell (2002) [Pubmed]
  11. Ubiquitin and SUMO systems in the regulation of mitotic checkpoints. Gutierrez, G.J., Ronai, Z. Trends Biochem. Sci. (2006) [Pubmed]
  12. Regulation of cyclin A-Cdk2 by SCF component Skp1 and F-box protein Skp2. Yam, C.H., Ng, R.W., Siu, W.Y., Lau, A.W., Poon, R.Y. Mol. Cell. Biol. (1999) [Pubmed]
  13. Characterization of the cullin and F-box protein partner Skp1. Ng, R.W., Arooz, T., Yam, C.H., Chan, I.W., Lau, A.W., Poon, R.Y. FEBS Lett. (1998) [Pubmed]
  14. Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Wei, W., Ayad, N.G., Wan, Y., Zhang, G.J., Kirschner, M.W., Kaelin, W.G. Nature (2004) [Pubmed]
  15. In vivo interference with Skp1 function leads to genetic instability and neoplastic transformation. Piva, R., Liu, J., Chiarle, R., Podda, A., Pagano, M., Inghirami, G. Mol. Cell. Biol. (2002) [Pubmed]
  16. Multiple Skp1-related proteins in Caenorhabditis elegans: diverse patterns of interaction with Cullins and F-box proteins. Yamanaka, A., Yada, M., Imaki, H., Koga, M., Ohshima, Y., Nakayama, K. Curr. Biol. (2002) [Pubmed]
  17. Five human genes encoding F-box proteins: chromosome mapping and analysis in human tumors. Chiaur, D.S., Murthy, S., Cenciarelli, C., Parks, W., Loda, M., Inghirami, G., Demetrick, D., Pagano, M. Cytogenet. Cell Genet. (2000) [Pubmed]
  18. CD28 costimulation mediates transcription of SKP2 and CKS1, the substrate recognition components of SCFSkp2 ubiquitin ligase that leads p27kip1 to degradation. Appleman, L.J., Chernova, I., Li, L., Boussiotis, V.A. Cell Cycle (2006) [Pubmed]
  19. Gene expression profiling of parkinsonian substantia nigra pars compacta; alterations in ubiquitin-proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhesion/cellular matrix and vesicle trafficking genes. Grünblatt, E., Mandel, S., Jacob-Hirsch, J., Zeligson, S., Amariglo, N., Rechavi, G., Li, J., Ravid, R., Roggendorf, W., Riederer, P., Youdim, M.B. Journal of neural transmission (Vienna, Austria : 1996) (2004) [Pubmed]
  20. Regulation of neddylation and deneddylation of cullin1 in SCFSkp2 ubiquitin ligase by F-box protein and substrate. Bornstein, G., Ganoth, D., Hershko, A. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  21. The SCF ubiquitin ligase protein slimb regulates centrosome duplication in Drosophila. Wojcik, E.J., Glover, D.M., Hays, T.S. Curr. Biol. (2000) [Pubmed]
  22. Role of epitope density in the induction of immunity and tolerance with thymus-independent antigens. II. Studies with 2,4-dinitrophenyl conjugates in vivo. Desaymard, C., Howard, J.G. Eur. J. Immunol. (1975) [Pubmed]
  23. Analysis of N-acyl aminonaphthalene sulphonic acid derivatives with potential anti-human immunodeficiency virus activity by thin-layer chromatography and flame ionization detection. Madelaine-Dupuich, C., Azema, J., Escoula, B., Rico, I., Lattes, A. Journal of chromatography. A. (1993) [Pubmed]
  24. Detection of cytoplasmic glycosylation associated with hydroxyproline. West, C.M., van der Wel, H., Blader, I.J. Meth. Enzymol. (2006) [Pubmed]
  25. In vitro osteogenesis from human skin-derived precursor cells. Buranasinsup, S., Sila-Asna, M., Bunyaratvej, N., Bunyaratvej, A. Dev. Growth Differ. (2006) [Pubmed]
  26. Cytoplasmic glycosylation of protein-hydroxyproline and its relationship to other glycosylation pathways. West, C.M., Van Der Wel, H., Sassi, S., Gaucher, E.A. Biochim. Biophys. Acta (2004) [Pubmed]
  27. Genomic organization and chromosomal localization of the human CUL2 gene and the role of von Hippel-Lindau tumor suppressor-binding protein (CUL2 and VBP1) mutation and loss in renal-cell carcinoma development. Clifford, S.C., Walsh, S., Hewson, K., Green, E.K., Brinke, A., Green, P.M., Gianelli, F., Eng, C., Maher, E.R. Genes Chromosomes Cancer (1999) [Pubmed]
  28. SKP2 associates with p130 and accelerates p130 ubiquitylation and degradation in human cells. Bhattacharya, S., Garriga, J., Calbó, J., Yong, T., Haines, D.S., Graña, X. Oncogene (2003) [Pubmed]
  29. HOS, a human homolog of Slimb, forms an SCF complex with Skp1 and Cullin1 and targets the phosphorylation-dependent degradation of IkappaB and beta-catenin. Fuchs, S.Y., Chen, A., Xiong, Y., Pan, Z.Q., Ronai, Z. Oncogene (1999) [Pubmed]
  30. Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage. Busino, L., Donzelli, M., Chiesa, M., Guardavaccaro, D., Ganoth, D., Dorrello, N.V., Hershko, A., Pagano, M., Draetta, G.F. Nature (2003) [Pubmed]
  31. OCP1, an F-box protein, co-localizes with OCP2/SKP1 in the cochlear epithelial gap junction region. Henzl, M.T., O'Neal, J., Killick, R., Thalmann, I., Thalmann, R. Hear. Res. (2001) [Pubmed]
  32. Mechanism of cell-cycle control: ligating the ligase. Lin, D.I., Diehl, J.A. Trends Biochem. Sci. (2004) [Pubmed]
  33. Phosphorylation- and Skp1-independent in vitro ubiquitination of E2F1 by multiple ROC-cullin ligases. Ohta, T., Xiong, Y. Cancer Res. (2001) [Pubmed]
  34. Identification of Elongin C and Skp1 sequences that determine Cullin selection. Yan, Q., Kamura, T., Cai, Y., Jin, J., Ivan, M., Mushegian, A., Conaway, R.C., Conaway, J.W. J. Biol. Chem. (2004) [Pubmed]
  35. von Hippel-Lindau disease. Maher, E.R., Kaelin, W.G. Medicine (Baltimore) (1997) [Pubmed]
  36. Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins. Fukuchi, M., Imamura, T., Chiba, T., Ebisawa, T., Kawabata, M., Tanaka, K., Miyazono, K. Mol. Biol. Cell (2001) [Pubmed]
  37. Molecular interactions of fission yeast Skp1 and its role in the DNA damage checkpoint. Lehmann, A., Katayama, S., Harrison, C., Dhut, S., Kitamura, K., McDonald, N., Toda, T. Genes Cells (2004) [Pubmed]
  38. Localization of organ of Corti protein II in the adult and developing gerbil cochlea. Yoho, E.R., Thomopoulos, G.N., Thalmann, I., Thalmann, R., Schulte, B.A. Hear. Res. (1997) [Pubmed]
  39. Interaction of Skp1 with CENP-E at the midbody is essential for cytokinesis. Liu, D., Zhang, N., Du, J., Cai, X., Zhu, M., Jin, C., Dou, Z., Feng, C., Yang, Y., Liu, L., Takeyasu, K., Xie, W., Yao, X. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  40. Surgical treatment of colon and rectum adenocarcinoma in elderly patients. Vivi, A.A., Lopes, A., Cavalcanti, S.d.e. .F., Rossi, B.M., Marques, L.A. Journal of surgical oncology. (1992) [Pubmed]
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