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Skp2  -  S-phase kinase-associated protein 2 (p45)

Mus musculus

Synonyms: 4930500A04Rik, Cyclin-A/CDK2-associated protein p45, F-box protein Skp2, F-box/WD-40 protein 1, FBXL1, ...
 
 
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Disease relevance of Skp2

  • METHODS: We constructed a plasmid vector, which synthesizes siRNAs to determine the effects of decreasing the high constitutive levels of Skp2 protein in melanoma cells [1].
  • The anti-sense effect was confirmed in two cell lines of oral cancer cells that also exhibited over-expression of the Skp2 protein [2].
  • Expression of the F-box protein SKP2 induces hyperplasia, dysplasia, and low-grade carcinoma in the mouse prostate [3].
  • Furthermore, intratumoral administration of adenovirus siRNA vector for Skp-2 efficiently inhibited growth of established subcutaneous tumor on NOD/SCID mice [4].
 

High impact information on Skp2

  • Skp2-dependent degradation of p27kip1 is essential for cell cycle progression [5].
  • Cks1 associates with the F box protein Skp2 and is essential for recognition of the p27Kip1 substrate for ubiquitination in vivo and in vitro [6].
  • Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro [7].
  • Although Skp2(-/-) animals are viable, cells in the mutant mice contain markedly enlarged nuclei with polyploidy and multiple centrosomes, and show a reduced growth rate and increased apoptosis [7].
  • Mice lacking Skp2, an F-box protein and substrate recognition component of an Skp1-Cullin-F-box protein (SCF) ubiquitin ligase, were generated [7].
 

Biological context of Skp2

  • The levels of Skp2 oscillate in the cell cycle, reaching a maximum in S phase [8].
  • Moreover, we show that cicaprost blocks the induction of Skp2 mRNA and that ectopic expression of a Skp2 cDNA overrides the effect of cicaprost on p27(Kip1) levels and S phase entry [9].
  • Antimitogenesis linked to regulation of Skp2 gene expression [9].
  • During differentiation processes, the onset of p27 expression was observed together with the down-regulation of Skp2 expression, in auditory epithelia [10].
  • The lack of p27 degradation in G(2) phase in Skp2(-/-) cells may thus result in suppression of Cdc2 activity and consequent inhibition of entry into M phase [11].
 

Anatomical context of Skp2

  • In contrast, an alteration of expression of p27 and Skp2 in the greater epithelial ridge and spiral ganglion appeared after differentiation of hair cells [10].
  • Hepatocytes of Skp2(-/-) mice entered the endoduplication cycle after mitogenic stimulation, whereas this phenotype was not apparent in Skp2(-/-)p27(-/-) mice [11].
  • Involvement of p27(KIP1) degradation by Skp2 in the regulation of proliferation in response to wounding of corneal epithelium [12].
  • Moreover, cyclin D1 expression was suppressed in Skp2 knockdown HeLa cells [13].
  • The first cell cycle of stimulated Skp2(-/-) lymphocytes appeared normal, but the second cycle was markedly inhibited, presumably as a result of p27(Kip1) accumulation during S-G(2) phases of the first cell cycle [14].
 

Associations of Skp2 with chemical compounds

  • Twenty-four hours after epithelial scraping in the Skp2(-/-) mice, the corneal epithelium was thinner than in wild-type mice and had many p27(KIP1)-positive cells and few BrdU-positive cells [12].
  • Skp2 mutants without the F-box or leucine rich repeat were not able to bind to Tob1 and did not enhance ubiquitination of Tob1 [13].
  • However, polyubiquitination activity was also detected in the cytoplasm of Skp2(-/-) cells, even with a threonine 187 --> alanine mutant of p27(Kip1) as substrate [14].
 

Regulatory relationships of Skp2

  • In contrast, the antisense oligonucleotide of Skp2 induced a further increase in the level of p27 [15].
 

Other interactions of Skp2

  • Cdc2-associated kinase activity was lower in Skp2(-/-) cells than in wild-type cells, and a reduction in Cdc2 activity was sufficient to induce overreplication [11].
  • Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication [7].
  • A novel route for connexin 43 to inhibit cell proliferation: negative regulation of S-phase kinase-associated protein (Skp 2) [15].
  • In the present study, we observed increased S-phase kinase-associated protein 2 mRNA expression in IL-16 null mice, but basal expression and activation-dependent regulation of p27(Kip1) were no different from wild-type mice [16].
  • Novel effect of helenalin on Akt signaling and Skp2 expression in 3T3-L1 preadipocytes [17].
  • These results indicate that the Skp2-mediated degradation pathway regulating the cellular degradation of p27 is essential for establishing beta cell mass and to respond to increased metabolic demand associated with insulin resistance [18].
 

Analytical, diagnostic and therapeutic context of Skp2

References

  1. Knockdown of Skp2 by siRNA inhibits melanoma cell growth in vitro and in vivo. Katagiri, Y., Hozumi, Y., Kondo, S. J. Dermatol. Sci. (2006) [Pubmed]
  2. Down-regulation of S-phase kinase associated protein 2 (Skp2) induces apoptosis in oral cancer cells. Harada, K., Supriatno, n.u.l.l., Kawashima, Y., Itashiki, Y., Yoshida, H., Sato, M. Oral Oncol. (2005) [Pubmed]
  3. Expression of the F-box protein SKP2 induces hyperplasia, dysplasia, and low-grade carcinoma in the mouse prostate. Shim, E.H., Johnson, L., Noh, H.L., Kim, Y.J., Sun, H., Zeiss, C., Zhang, H. Cancer Res. (2003) [Pubmed]
  4. Gene therapy for human small-cell lung carcinoma by inactivation of Skp-2 with virally mediated RNA interference. Sumimoto, H., Yamagata, S., Shimizu, A., Miyoshi, H., Mizuguchi, H., Hayakawa, T., Miyagishi, M., Taira, K., Kawakami, Y. Gene Ther. (2005) [Pubmed]
  5. Skp2-dependent degradation of p27kip1 is essential for cell cycle progression. Kossatz, U., Dietrich, N., Zender, L., Buer, J., Manns, M.P., Malek, N.P. Genes Dev. (2004) [Pubmed]
  6. A CDK-independent function of mammalian Cks1: targeting of SCF(Skp2) to the CDK inhibitor p27Kip1. Spruck, C., Strohmaier, H., Watson, M., Smith, A.P., Ryan, A., Krek, T.W., Reed, S.I. Mol. Cell (2001) [Pubmed]
  7. Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication. Nakayama, K., Nagahama, H., Minamishima, Y.A., Matsumoto, M., Nakamichi, I., Kitagawa, K., Shirane, M., Tsunematsu, R., Tsukiyama, T., Ishida, N., Kitagawa, M., Nakayama, K., Hatakeyama, S. EMBO J. (2000) [Pubmed]
  8. Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase. Bornstein, G., Bloom, J., Sitry-Shevah, D., Nakayama, K., Pagano, M., Hershko, A. J. Biol. Chem. (2003) [Pubmed]
  9. Antimitogenesis linked to regulation of Skp2 gene expression. Stewart, S.A., Kothapalli, D., Yung, Y., Assoian, R.K. J. Biol. Chem. (2004) [Pubmed]
  10. Role of the F-box protein Skp2 in cell proliferation in the developing auditory system in mice. Dong, Y., Nakagawa, T., Endo, T., Kim, T.S., Iguchi, F., Yamamoto, N., Naito, Y., Ito, J. Neuroreport (2003) [Pubmed]
  11. Skp2-mediated degradation of p27 regulates progression into mitosis. Nakayama, K., Nagahama, H., Minamishima, Y.A., Miyake, S., Ishida, N., Hatakeyama, S., Kitagawa, M., Iemura, S., Natsume, T., Nakayama, K.I. Dev. Cell (2004) [Pubmed]
  12. Involvement of p27(KIP1) degradation by Skp2 in the regulation of proliferation in response to wounding of corneal epithelium. Yoshida, K., Nakayama, K., Nagahama, H., Harada, T., Harada, C., Imaki, J., Matsuda, A., Yamamoto, K., Ito, M., Ohno, S., Nakayama, K. Invest. Ophthalmol. Vis. Sci. (2002) [Pubmed]
  13. Degradation of Tob1 Mediated by SCFSkp2-Dependent Ubiquitination. Hiramatsu, Y., Kitagawa, K., Suzuki, T., Uchida, C., Hattori, T., Kikuchi, H., Oda, T., Hatakeyama, S., Nakayama, K.I., Yamamoto, T., Konno, H., Kitagawa, M. Cancer Res. (2006) [Pubmed]
  14. Degradation of p27(Kip1) at the G(0)-G(1) transition mediated by a Skp2-independent ubiquitination pathway. Hara, T., Kamura, T., Nakayama, K., Oshikawa, K., Hatakeyama, S., Nakayama, K. J. Biol. Chem. (2001) [Pubmed]
  15. A novel route for connexin 43 to inhibit cell proliferation: negative regulation of S-phase kinase-associated protein (Skp 2). Zhang, Y.W., Nakayama, K., Nakayama, K., Morita, I. Cancer Res. (2003) [Pubmed]
  16. Pro-IL-16 regulation in activated murine CD4+ lymphocytes. Ren, F., Zhan, X., Martens, G., Lee, J., Center, D., Hanson, S.K., Kornfeld, H. J. Immunol. (2005) [Pubmed]
  17. Novel effect of helenalin on Akt signaling and Skp2 expression in 3T3-L1 preadipocytes. Auld, C.A., Hopkins, R.G., Fernandes, K.M., Morrison, R.F. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  18. Essential role of Skp2-mediated p27 degradation in growth and adaptive expansion of pancreatic beta cells. Zhong, L., Georgia, S., Tschen, S.I., Nakayama, K., Nakayama, K., Bhushan, A. J. Clin. Invest. (2007) [Pubmed]
  19. Recovery of liver mass without proliferation of hepatocytes after partial hepatectomy in Skp2-deficient mice. Minamishima, Y.A., Nakayama, K., Nakayama, K. Cancer Res. (2002) [Pubmed]
  20. Cell cycle-dependent regulation of the Skp2 promoter by GA-binding protein. Imaki, H., Nakayama, K., Delehouzee, S., Handa, H., Kitagawa, M., Kamura, T., Nakayama, K.I. Cancer Res. (2003) [Pubmed]
 
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