Once a protein is implicated in cancer, it is next important to define its role in cancer and how it functions in cancer. Skp2 is an F-box protein of the SCF(Skp2) ubiquitin ligase complex targeting p27Kip1 for ubiquitination. In clinical cancer samples, reduction of p27 and increase in Skp2 are frequent and generally associated events. The conventional view at present is that Skp2 functions as an oncoprotein by targeting p27 for ubiquitination and degradation and, accordingly, the function of SCF(Skp2) to ubiquitinate p27 has been the target of drug development efforts. More recent studies however have indicated the needs to more carefully study the significance of p27 ubiquitination by SCF(Skp2) in tumorigenesis. We have recently determined that Skp2 binds to the N-terminus of cyclin A to directly protect it from inhibition by p27 family CKIs;and a blocking peptide for Skp2-cyclin A interaction can selectively induce cancer cell death in culture. These findings led us to hypothesize that binding to cyclin A is an important function of Skp2 in cancer. In this project, we propose to use our recent discovery that Skp2 plays an essential role in Rb deficiency-induced pituitary and thyroid tumorigenesis to determine the roles of SCF(Skp2)-mediated p27 ubiquitination and binding to cyclin A in Skp2 function in this tumor model. ENU-induced tumorigenesis will be used to extend these studies to a tumor model involving multiple organs. Further, we will use mouse embryo and biochemical studies as well as genetic studies to determine how Skp2 function and Rb function integrate to sustain Rb-deficient cells for tumorigenesis in the presence of Skp2, and to eliminate Rb-deficient cells when Skp2 is inactivated. Results from these studies will elucidate the roles and functional mechanisms of the tumor suppressor Rb, oncogene Skp2, and their relationship in normal physiology and in cancer to reveal therapeutic targets.

Public Health Relevance

A common feature of cancer cells is that they contain abundant amounts of the protein Skp2. This project will determine how Skp2 functions in cancer and to identify ways to inactivate it.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
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Hildesheim, Jeffrey
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Albert Einstein College of Medicine
Anatomy/Cell Biology
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United States
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Zhao, H; Lu, Z; Bauzon, F et al. (2017) p27T187A knockin identifies Skp2/Cks1 pocket inhibitors for advanced prostate cancer. Oncogene 36:60-70
Zhao, Hongling; Wang, Hongbo; Bauzon, Frederick et al. (2016) Deletions of Retinoblastoma 1 (Rb1) and Its Repressing Target S Phase Kinase-associated protein 2 (Skp2) Are Synthetic Lethal in Mouse Embryogenesis. J Biol Chem 291:10201-9
Zhao, Hongling; Bauzon, Frederick; Bi, Enguang et al. (2015) Substituting threonine 187 with alanine in p27Kip1 prevents pituitary tumorigenesis by two-hit loss of Rb1 and enhances humoral immunity in old age. J Biol Chem 290:5797-809
Zhu, L; Lu, Z; Zhao, H (2015) Antitumor mechanisms when pRb and p53 are genetically inactivated. Oncogene 34:4547-57
Lu, Zhonglei; Bauzon, Frederick; Fu, Hao et al. (2014) Skp2 suppresses apoptosis in Rb1-deficient tumours by limiting E2F1 activity. Nat Commun 5:3463
Zhao, Hongling; Bauzon, Frederick; Fu, Hao et al. (2013) Skp2 deletion unmasks a p27 safeguard that blocks tumorigenesis in the absence of pRb and p53 tumor suppressors. Cancer Cell 24:645-59
Lu, Zhonglei; Marcelin, Genevieve; Bauzon, Frederick et al. (2013) pRb is an obesity suppressor in hypothalamus and high-fat diet inhibits pRb in this location. EMBO J 32:844-57
Bauzon, Frederick; Zhu, Liang (2010) Racing to block tumorigenesis after pRb loss: an innocuous point mutation wins with synthetic lethality. Cell Cycle 9:2118-23
Wang, Hongbo; Cui, Jinhua; Bauzon, Frederick et al. (2010) A comparison between Skp2 and FOXO1 for their cytoplasmic localization by Akt1. Cell Cycle 9:1021-2
Wang, Hongbo; Bauzon, Frederick; Ji, Peng et al. (2010) Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/- mice. Nat Genet 42:83-8

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