# F-Box Proteins: Deregulated Cell Cycle Control and Proteolysis in Cancer

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $464,613

## Abstract

PROJECT ABSTRACT / SUMMARY
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 βTrCP)
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-κB), 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.

## Key facts

- **NIH application ID:** 9868283
- **Project number:** 5R01CA076584-22
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** MICHELE PAGANO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $464,613
- **Award type:** 5
- **Project period:** 1998-07-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868283

## Citation

> US National Institutes of Health, RePORTER application 9868283, F-Box Proteins: Deregulated Cell Cycle Control and Proteolysis in Cancer (5R01CA076584-22). Retrieved via AI Analytics 2026-05-31 from https://api.ai-analytics.org/grant/nih/9868283. Licensed CC0.

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