SKP1?CUL1?F-box protein (SCF) ubiquitin ligase complexes use a family of F-box proteins (69 in humans) as substrate receptors to mediate the ubiquitylation and consequent degradation of a large number of regulatory proteins involved in many cellular processes. Given their critical role within the three key dimensions of cellular life: growth, survival, and proliferation, deregulation of SCF complexes and their substrates contribute to oncogenic events. SCFs can function as oncoproteins when overexpressed (if their substrates are tumor suppressors) or as tumor suppressors (if their substrates are oncoproteins). Several F-box proteins play an established role in cancer (e.g., FBXW7, FBXO11, FBXL1, and FBXW1), and inhibitors have been developed, with thalidomide and lenalidomide (which modulate CRBN, an F-box protein- related substrate receptor) as clinically valuable examples. During the initial years of CA076584, we focused on the role played by FBXL1 (aka SKP2) in cancer and defined FBXL1 as an oncogene in a wide variety of tumors. Moreover, our studies on FBXW1 (aka ?TrCP) demonstrated a role for this F-box protein in mammary gland development and tumorigenesis. During the last funding cycle, we asked whether any other members of the F-box protein family play important roles in cancer. We have uncovered a unique role for FBXW7 in the survival of multiple myeloma cells (by contributing to the activation of NF-?B), and found that FBXO11 is a tumor suppressor in Diffuse Large B-Cell Lymphomas (by mediating the proteolysis of BCL6). We now propose a project investigating F-box protein-controlled cell cycle checkpoints and their aberrations in cancer cells. Using protein purifications followed by mass spectrometry analysis, we have identified novel players involved in these processes and we will characterize the mechanism and regulation of their degradation in the context of genotoxic stress in S and G2 cells (Aims 1 and 2). Several features of cancer cells suggest that their defects in DNA repair provide the required therapeutic index that make them sensitive to PARP inhibitors.
Specific Aim 3 has two objectives: (i) to identify the SCF defects that sensitize cancer cells to this and related approaches, and (ii) to establish cell systems and mouse models to optimize and validate the concept of exploiting these defects in cancer therapy.
/RELEVANCE Deregulation of F-box proteins and their substrates contributes to malignant transformation since the misregulated degradation of tumor suppressors or oncoproteins can drive tumorigenesis. The clinical success of thalidomide and lenalidomide (two small molecules targeting CRBN, a substrate receptor related to F-box proteins), which are used in the treatment of multiple myeloma, suggests the potential to develop drugs targeting F-box proteins. The goal of CA076584 is to understand the functions of key F-box proteins whose deregulation contributes to the oncogenic phenotype, and develop a novel therapeutic strategy that exploits these aberrations to kill cancer cells.
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