title: The role of Skp2 and its substrate CDKN1B (p27) in colorectal cancer.
abstract: Colorectal cancer is one of the most frequent cancers worldwide, having the fourth mortality rate among cancers in both sexes. Numerous studies are investigating the signalling pathways and different factors involved in the development and progression of colorectal cancer. It has recently been shown that the S-phase kinase-associated protein 2 (Skp2) overexpression plays an important role in the pathogenesis of colorectal cancer. We review the role of Skp2 and its ubiquitin-proteasome pathway in colorectal cancer. The F-box protein Skp2, a component of the SCF (Skp1-Cullin 1-F-box) E3 ubiquitin-ligase complex, has been shown to regulate cellular proliferation, cancer progression and metastasis by targeting several cell cycle regulators for ubiquitination and subsequent 26S proteasome degradation. The best known protein substrate of the Skp2 is the cyclin-dependent kinase inhibitor 1B (CDKN1B), also known as p27Kip1. Overexpression of Skp2 and loss of CDKN1B (p27) was strongly associated with aggressive tumor behavior and poor clinical outcome in a variety of cancers, including colorectal cancer. An efficient interaction between Skp2 and CDKN1B (p27) requires the presence of an essential activator of the SCF-Skp2 complex, the cyclin-dependent kinase subunit 1 (Cks1) cofactor. Alterations in the Skp2, Cks1 and CDKN1B (p27) expression have major effects on colorectal carcinogenesis and may serve as an important and independent prognostic marker. Furthermore, we highlight that Skp2 may be a promising therapeutic target for colorectal cancer, and development of Skp2 inhibitors would have a great impact on colorectal cancer therapy.
authors.affiliation: Prof. Dr. Ion Chiricuta Institute of Oncology; Iuliu Hatieganu University of Medicine and Pharmacy, Department of Immunology, Research Center for Functional Genomics, Biomedicine and Translational Medicine Cluj Napoca, Romania. Bochis.Ovidiu@umfcluj.ro.
authors.forename: Ovidiu V
authors.initials: OV
authors.lastname: Bochis
authors.affiliation: Prof. Dr. Ion Chiricuta Institute of Oncology; Iuliu Hatieganu University of Medicine and Pharmacy, Department of Immunology, Research Center for Functional Genomics, Biomedicine and Translational Medicine Cluj Napoca, Romania.
authors.forename: Alexandru
authors.initials: A
authors.lastname: Irimie
authors.affiliation: Division of Oncology, Medical University of Graz, Graz, Austria; M.D. Anderson Cancer Center, Department of Experimental Therapeutics, Houston, TX, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Pichler
authors.affiliation: Prof. Dr. Ion Chiricuta Institute of Oncology; Iuliu Hatieganu University of Medicine and Pharmacy, Department of Immunology, Research Center for Functional Genomics, Biomedicine and Translational Medicine Cluj Napoca, Romania; M.D. Anderson Cancer Center, Department of Experimental Therapeutics, Houston, TX , USA.
authors.forename: Ioana
authors.initials: I
authors.lastname: Berindan-Neagoe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D058990:Molecular Targeted Therapy; D044786:S-Phase Kinase-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; C436291:CDKN1B protein, human; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27