Genomes and Genes
s phase kinase associated proteins
Summary: A family of structurally-related proteins that were originally identified by their ability to complex with cyclin proteins (CYCLINS). They share a common domain that binds specifically to F-BOX MOTIFS. They take part in SKP CULLIN F-BOX PROTEIN LIGASES, where they can bind to a variety of F-BOX PROTEINS.
- Bar On O, Shapira M, Hershko D. Differential effects of doxorubicin treatment on cell cycle arrest and Skp2 expression in breast cancer cells. Anticancer Drugs. 2007;18:1113-21 pubmed
- Kitajima S, Kudo Y, Ogawa I, Bashir T, Kitagawa M, Miyauchi M, et al. Role of Cks1 overexpression in oral squamous cell carcinomas: cooperation with Skp2 in promoting p27 degradation. Am J Pathol. 2004;165:2147-55 pubmed..These findings suggest that Cks1 overexpression may play an important role for OSCC development through Skp2-mediated p27 degradation, and that Cks1 siRNA can be a novel modality of gene therapy. ..
- Hara T, Kamura T, Oshikawa K, Hatakeyama S, Nakayama K. Degradation of p27(Kip1) at the G(0)-G(1) transition mediated by a Skp2-independent ubiquitination pathway. J Biol Chem. 2001;276:48937-43 pubmed..These results suggest that a polyubiquitination activity in the cytoplasm contributes to the early phase of p27(Kip1) degradation in a Skp2-independent manner, thereby promoting cell cycle progression from G(0) to G(1). ..
- Grimmler M, Wang Y, Mund T, Cilensek Z, Keidel E, Waddell M, et al. Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases. Cell. 2007;128:269-80 pubmed
- Bond M, Sala Newby G, Newby A. Focal adhesion kinase (FAK)-dependent regulation of S-phase kinase-associated protein-2 (Skp-2) stability. A novel mechanism regulating smooth muscle cell proliferation. J Biol Chem. 2004;279:37304-10 pubmed..Taken together, these data demonstrate that the vascular ECM controls SMC proliferation via FAK-dependent regulation of Skp-2 protein stability. ..
- 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..Our results suggest that SKP2 may be involved in progression of NSCLC, and that targeting this molecule could represent a promising therapeutic option. ..
- 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..Furthermore, expression of the FOXO1 protein is lost in a mouse lymphoma model, where Skp2 is overexpressed. These data suggest that the Skp2-promoted proteolysis of FOXO1 plays a key role in tumorigenesis. ..
- Pène F, Claessens Y, Muller O, Viguie F, Mayeux P, Dreyfus F, et al. Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene. 2002;21:6587-97 pubmed..Moreover, constitutive activation of this pathway is a frequent event in the biology of MM in vivo and may be more frequently observed in PCL. ..
- 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..Consequently, the SKP2 pathway may be a suitable target for novel prostate cancer therapies. ..
- Bond M, Wu Y, Sala Newby G, Newby A. Rho GTPase, Rac1, regulates Skp2 levels, vascular smooth muscle cell proliferation, and intima formation in vitro and in vivo. Cardiovasc Res. 2008;80:290-8 pubmed publisher..We investigated the role of Rac(1) in the regulation of Skp2 in rat VSMC...
- 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..These findings provide an insight into the orchestration of SCF and APC activities during cell-cycle progression, and into the involvement of the APC in G1. ..
- Ezoe S, Matsumura I, Nakata S, Gale K, Ishihara K, Minegishi N, et al. GATA-2/estrogen receptor chimera regulates cytokine-dependent growth of hematopoietic cells through accumulation of p21(WAF1) and p27(Kip1) proteins. Blood. 2002;100:3512-20 pubmed..These results suggest that GATA-2 may regulate expression levels of p21(WAF1) and p27(Kip1), thereby contributing to the quiescence of hematopoietic stem/progenitor cells. ..
- Kudo Y, Kitajima S, Sato S, Miyauchi M, Ogawa I, Takata T. High expression of S-phase kinase-interacting protein 2, human F-box protein, correlates with poor prognosis in oral squamous cell carcinomas. Cancer Res. 2001;61:7044-7 pubmed
- Piva R, Liu J, Chiarle R, Podda A, Pagano M, Inghirami G. In vivo interference with Skp1 function leads to genetic instability and neoplastic transformation. Mol Cell Biol. 2002;22:8375-87 pubmed..Our findings support a crucial role for Skp1 in proper chromosomal segregation, which is required for the maintenance of euploidy and suppression of transformation. ..
- Timmerbeul I, Garrett Engele C, Kossatz U, Chen X, Firpo E, Grünwald V, et al. Testing the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer. Proc Natl Acad Sci U S A. 2006;103:14009-14 pubmed..These studies may guide the choice of clinical settings in which pharmacologic inhibitors of the Skp2 pathway might be of therapeutic value. ..
- Malek N, Sundberg H, McGrew S, Nakayama K, Kyriakides T, Roberts J, et al. A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase. Nature. 2001;413:323-7 pubmed..Our efforts to explain this unexpected result led to the discovery of a second proteolytic pathway for controlling p27, one that is activated by mitogens and degrades p27 exclusively during G1. ..
- 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..The structure and biochemical data support the proposed model that Cdk2-cyclin A contributes to the recruitment of p27(Kip1) to the SCF(Skp2)-Cks1 complex. ..
- 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..The results reveal an unexpected physical convergence between the pRB tumour-suppressor protein and E3 ligase complexes, and raise the possibility that pRB may direct APC/C to additional targets during pRB-mediated cell-cycle exit. ..
- Zhang L, Wang C. F-box protein Skp2: a novel transcriptional target of E2F. Oncogene. 2006;25:2615-27 pubmed..These results reveal Skp2 as a novel target for E2F regulation that is disrupted in several human tumor cell lines. ..
- Yokoi S, Yasui K, Saito Ohara F, Koshikawa K, Iizasa T, Fujisawa T, et al. A novel target gene, SKP2, within the 5p13 amplicon that is frequently detected in small cell lung cancers. Am J Pathol. 2002;161:207-16 pubmed..Our results indicate that SKP2 is likely to be a target of the 5p13 amplification and to play an important role in the growth of SCLC cells. ..
- Seeliger M, Breward S, Friedler A, Schon O, Itzhaki L. Cooperative organization in a macromolecular complex. Nat Struct Biol. 2003;10:718-24 pubmed..Simultaneous and synergistic binding of multiple subunits in a complex provides the specificity and control required before the key cell-cycle regulator p27 is committed to degradation. ..
- Schiffer D, Cavalla P, Fiano V, Ghimenti C, Piva R. Inverse relationship between p27/Kip.1 and the F-box protein Skp2 in human astrocytic gliomas by immunohistochemistry and Western blot. Neurosci Lett. 2002;328:125-8 pubmed..1 degradation. ..
- Goto A, Niki T, Moriyama S, Funata N, Moriyama H, Nishimura Y, et al. Immunohistochemical study of Skp2 and Jab1, two key molecules in the degradation of P27, in lung adenocarcinoma. Pathol Int. 2004;54:675-81 pubmed..Thus, Skp2 and Jab1 regulate P27 degradation, and might contribute to the development and progression of lung AD through P27-mediated and -unmediated mechanisms. ..
- Shapira M, Ben Izhak O, Linn S, Futerman B, Minkov I, Hershko D. The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma. Cancer. 2005;103:1336-46 pubmed..Results suggest that overexpression of Skp2 or Cks1 is strongly associated with poor prognosis and may thus be used as prognostic markers for overall survival in colorectal carcinoma. ..
- Musat M, Korbonits M, Pyle M, Gueorguiev M, Kola B, Morris D, et al. The expression of the F-box protein Skp2 is negatively associated with p27 expression in human pituitary tumors. Pituitary. 2002;5:235-42 pubmed..Our data suggest that increased p27 degradation through the ubiquitin-proteasome pathway could be regulated in pituitary tumors by changes in Skp2 expression, although other factors probably also play a role. ..
- Yoshida K, Nakayama K, Nagahama H, Harada T, Harada C, Imaki J, et al. Involvement of p27(KIP1) degradation by Skp2 in the regulation of proliferation in response to wounding of corneal epithelium. Invest Ophthalmol Vis Sci. 2002;43:364-70 pubmed..These results suggest that degradation of p27(KIP1) by Skp2 is involved in the regulation of cell proliferation in response to wounding of the corneal epithelium. ..
- Reichert M, Saur D, Hamacher R, Schmid R, Schneider G. Phosphoinositide-3-kinase signaling controls S-phase kinase-associated protein 2 transcription via E2F1 in pancreatic ductal adenocarcinoma cells. Cancer Res. 2007;67:4149-56 pubmed..The complex and profound connection of PI3K/AKT1 signaling to the cell cycle qualifies this pathway as a suitable target for therapeutic intervention in PDAC. ..
- Shigemasa K, Gu L, O Brien T, Ohama K. Skp2 overexpression is a prognostic factor in patients with ovarian adenocarcinoma. Clin Cancer Res. 2003;9:1756-63 pubmed..Skp2 expression might play an important role in the development and progression of ovarian adenocarcinomas, and Skp2 overexpression is an independent prognostic marker of ovarian adenocarcinoma patients. ..
- Ganiatsas S, Dow R, Thompson A, Schulman B, Germain D. A splice variant of Skp2 is retained in the cytoplasm and fails to direct cyclin D1 ubiquitination in the uterine cancer cell line SK-UT. Oncogene. 2001;20:3641-50 pubmed..Finally, our data indicates that differential splicing of F-box proteins may represent an additional level of regulation of the F-box mediated ubiquitination pathway. ..
- 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..In long-term follow-up, high Skp2 and low p27 indicate an unfavorable course. Beyond the prognostic importance of the Skp2/p27 index, it could serve as a predictive marker for new molecular targeted therapies aiming at Skp2. ..
- Nakayama K, Nakayama K. Regulation of the cell cycle by SCF-type ubiquitin ligases. Semin Cell Dev Biol. 2005;16:323-33 pubmed..Clinical evidence also suggests that dysregulation of these F-box proteins contributes to human cancers. ..
- 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..The absence of this relationship in aggressive lymphomas suggests that other factors contribute to deregulation of p27(Kip1) expression in these tumors. ..
- Kim S, Herbst A, Tworkowski K, Salghetti S, Tansey W. Skp2 regulates Myc protein stability and activity. Mol Cell. 2003;11:1177-88 pubmed..These data suggest that Skp2 functions to connect Myc activity and destruction, and reveal an unexpected oncoprotein connection that may play an important role in controlling cell growth in normal and cancer cells. ..
- 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 results suggest that Skp2 is a transcriptional cofactor for c-Myc and indicates a close relationship between transcription activation and transcription factor ubiquitination. ..
- 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..Thus, overexpression of Skp2 is associated with colorectal carcinogenesis and late metastasis to lymph nodes, whereas relative reduction of Skp2 is correlated with local invasion of primary carcinoma. ..
- 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..These results identify an Rb-Skp2-p27 pathway in Rb function, which may be involved in inhibition of tumor progression. ..
- Langner C, von Wasielewski R, Ratschek M, Rehak P, Zigeuner R. Biological significance of p27 and Skp2 expression in renal cell carcinoma. A systematic analysis of primary and metastatic tumour tissues using a tissue microarray technique. Virchows Arch. 2004;445:631-6 pubmed..In conclusion, p27 and Skp2 proved to be additional biomarkers in renal cancer pathology with both prognostic and diagnostic impact. ..
- Hershko D. Oncogenic properties and prognostic implications of the ubiquitin ligase Skp2 in cancer. Cancer. 2008;112:1415-24 pubmed publisher..Skp2 may be an attractive target for the development of novel interventional therapy. ..
- 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..Thus far, there is no specific therapy for the ER-negative and HER-2/neu resistant groups, which are among the subset of aggressive tumors. ..
- Sitry D, Seeliger M, Ko T, Ganoth D, Breward S, Itzhaki L, et al. Three different binding sites of Cks1 are required for p27-ubiquitin ligation. J Biol Chem. 2002;277:42233-40 pubmed..The interaction of Skp2 with the substrate is further strengthened by the association of the Cdk-binding site of Cks1 with Cdk2/cyclin E, to which phosphorylated p27 is bound. ..
- Imaki H, Nakayama K, Delehouzee S, Handa H, Kitagawa M, Kamura T, et al. Cell cycle-dependent regulation of the Skp2 promoter by GA-binding protein. Cancer Res. 2003;63:4607-13 pubmed..These data suggest that the cell cycle-dependent binding of GABP to the Skp2 promoter plays an important role in the regulation of Skp2 expression and cell cycle progression from G(1) to S phase. ..
- 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..We propose that p107, in addition to its interaction with E2F, inhibits cell proliferation through the control of Skp2 expression and the resulting stabilization of p27. ..
- 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..These findings reveal a new functional mechanism of Skp2 and a new regulatory mechanism of cyclin A. ..
- Zhong L, Georgia S, Tschen S, Nakayama K, Nakayama K, Bhushan A. Essential role of Skp2-mediated p27 degradation in growth and adaptive expansion of pancreatic beta cells. J Clin Invest. 2007;117:2869-76 pubmed..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. ..
- Bond M, Sala Newby G, Wu Y, Newby A. Biphasic effect of p21Cip1 on smooth muscle cell proliferation: role of PI 3-kinase and Skp2-mediated degradation. Cardiovasc Res. 2006;69:198-206 pubmed..Low levels of p21Cip1 are also essential to counter apoptosis during cell-cycle progression. ..
- Lin H, Chuang L, Boix Perales H, Philpott A, Yew P. Ubiquitination of cyclin-dependent kinase inhibitor, Xic1, is mediated by the Xenopus F-box protein xSkp2. Cell Cycle. 2006;5:304-14 pubmed..These studies provide the first characterization of the SCF in Xenopus and its role in the ubiquitination of CDK inhibitor, Xic1, during DNA replication initiation. ..
- Hershko D, Shapira M. Prognostic role of p27Kip1 deregulation in colorectal cancer. Cancer. 2006;107:668-75 pubmed
- Wu Y, Bond M, Sala Newby G, Newby A. Altered S-phase kinase-associated protein-2 levels are a major mediator of cyclic nucleotide-induced inhibition of vascular smooth muscle cell proliferation. Circ Res. 2006;98:1141-50 pubmed..These data demonstrate for the first time that Skp2 is an important factor in VSMC proliferation and its inhibition by cyclic nucleotides. ..
- Wang F, Qi L, Su Y, Yan Q, Teng Y. Inhibition of cell proliferation of Tenon's capsule fibroblast by S-phase kinase-interacting protein 2 targeting SiRNA through increasing p27 protein level. Invest Ophthalmol Vis Sci. 2010;51:1475-82 pubmed publisher..In the present study, the authors investigated whether small interfering RNA (siRNA)-mediated gene silencing of Skp2 can be used to increase p27(kip1) level and inhibit cell proliferation in rabbit Tenon's capsule fibroblast (rTF)...
- Amati B. Myc degradation: dancing with ubiquitin ligases. Proc Natl Acad Sci U S A. 2004;101:8843-4 pubmed
- Stewart S, Kothapalli D, Yung Y, Assoian R. Antimitogenesis linked to regulation of Skp2 gene expression. J Biol Chem. 2004;279:29109-13 pubmed..Our data show that inhibition of F-box protein gene expression can underlie the effect of a potent antimitogen. ..
- Ben Izhak O, Lahav Baratz S, Meretyk S, Ben Eliezer S, Sabo E, Dirnfeld M, et al. Inverse relationship between Skp2 ubiquitin ligase and the cyclin dependent kinase inhibitor p27Kip1 in prostate cancer. J Urol. 2003;170:241-5 pubmed..Skp2 expression in prostate biopsies may be used as an additional marker for tumor aggressiveness. The results also suggest a role for Skp2 in the pathogenesis of prostate malignancy. ..
- 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..Margin status and intrinsic property of myxofibrosarcomas both affect patient survival. Skp2 overexpression is highly representative of the biological aggressiveness of myxofibrosarcomas and plays an important prognostic role. ..
- Kamata Y, Watanabe J, Nishimura Y, Arai T, Kawaguchi M, Hattori M, et al. High expression of skp2 correlates with poor prognosis in endometrial endometrioid adenocarcinoma. J Cancer Res Clin Oncol. 2005;131:591-6 pubmed..The skp2 level might have increased due to p27 accumulation and may be a good indicator of proliferative activity and poor prognosis. ..
- 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 presence of a positive correlation between Skp2 and phosphorylated PTEN suggests that an aberration in the PTEN/Skp2 signaling pathway might be operating in AML. ..
- Nakayama K, Nagahama H, Minamishima Y, Miyake S, Ishida N, Hatakeyama S, et al. Skp2-mediated degradation of p27 regulates progression into mitosis. Dev Cell. 2004;6:661-72 pubmed..These data suggest that p27 proteolysis is necessary for the activation of not only Cdk2 but also Cdc2, and that Skp2 contributes to regulation of G(2)-M progression by mediating the degradation of p27. ..
- Wang W, Ungermannova D, Jin J, Harper J, Liu X. Negative regulation of SCFSkp2 ubiquitin ligase by TGF-beta signaling. Oncogene. 2004;23:1064-75 pubmed
- Jin J, Harper J. A license to kill: transcriptional activation and enhanced turnover of Myc by the SCF(kp2) ubiquitin ligase. Cancer Cell. 2003;3:517-8 pubmed
- Shim E, Johnson L, Noh H, Kim Y, Sun H, Zeiss C, et al. Expression of the F-box protein SKP2 induces hyperplasia, dysplasia, and low-grade carcinoma in the mouse prostate. Cancer Res. 2003;63:1583-8 pubmed..Our data suggest that SKP2 acts as an oncoprotein in the mouse prostate gland, probably through its function as a limiting factor for ubiquitin-dependent degradation of p27. ..
- Dong Y, Sui L, Watanabe Y, Sugimoto K, Tokuda M. S-phase kinase-associated protein 2 expression in laryngeal squamous cell carcinomas and its prognostic implications. Oncol Rep. 2003;10:321-5 pubmed..These findings indicated that Skp2 expression was closely associated with tumor progression and represented an independent marker for prognosis of LSCC. ..
- Yokoi S, Yasui K, Iizasa T, Takahashi T, Fujisawa T, Inazawa J. Down-regulation of SKP2 induces apoptosis in lung-cancer cells. Cancer Sci. 2003;94:344-9 pubmed
- 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..Our data conclude an essential post-translational regulation of MLL by the cell cycle ubiquitin/proteasome system (UPS) assures the temporal necessity of MLL in coordinating cell cycle progression. ..
- Oliveira A, Okuno S, Nascimento A, Lloyd R. Skp2 protein expression in soft tissue sarcomas. J Clin Oncol. 2003;21:722-7 pubmed..The lack of an inverse correlation between Skp2 and p27 suggests that additional molecular events associated with either Skp2 expression or p27 proteolysis may be operating in these tumors. ..