# K63-Ubiquitin-mediated cell signal regulation in epidermis

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $354,200

## Abstract

ABSTRACT
 Epidermis and its appendages constitute the outermost skin barrier essential for mammalian health and
survival. Dysregulation of cell signaling in epidermal cells involving NF-κB, AP1, and c-Myc gene regulators
can lead to local and systemic disorders, as well as cancer. Nevertheless, direct targeting of these core
transcription factors has been proven technically challenging, prohibiting a meaningful clinical translation. Our
long-term objective is to explore how K63-Ubiquitin (K63-Ub)-mediated signals converge on gene regulation
and can be rationally targeted for therapy of inflammatory and neoplastic skin disorders. Towards this end, our
recent efforts are focused on characterizing novel functions of CYLD, a K63-Ub protease whose loss-of-
function is linked to immunological diseases, infertility, and benign and malignant neoplasms. While mutant
Cyld in humans leads to Cyldm-syndrome characterized by widespread and recurrent epidermal and
appendage tumors, understanding the complete role of CYLD is hampered by the lack of a clinically relevant
disease model. To uncover novel disease mechanisms we have generated a mouse model that recapitulates
genetic and phenotypic features of human Cyldm-syndrome. Using this animal model, we have identified c-Myc
as a new CYLD substrate, UBE2N as an upstream regulator of c-Myc and androgen signaling, in addition to a
role of CYLD in the regulation of the NF-κB and AP1 pathways. These findings highlight the broad impact of
CYLD and the utility of the Cyldm skin model for increasing our understanding of novel disease mechanisms.
 This study is designed based on the hypothesis that unopposed UBE2N function in epithelial cells
promotes inflammation and c-Myc-dependent skin defects. We propose three specific aims: 1) to define
the role of c-Myc in Cyldm skin; 2) to determine the molecular mechanisms underlying K63-Ub-mediated c-Myc
activation; and 3) to determine the functions of UBE2N in epidermal proliferation and tumorigenesis. We will
utilize mouse and human skin tissue models, as well as cutting-edge technologies for gene editing,
transcriptome and protein interactome analyses. Completion of these studies will reveal novel molecular
mechanisms of epidermal morphogenesis and provide therapeutic insights for skin inflammation and cancer.

## Key facts

- **NIH application ID:** 9903230
- **Project number:** 5R01AR073858-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Jennifer Yunyan Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,200
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903230

## Citation

> US National Institutes of Health, RePORTER application 9903230, K63-Ubiquitin-mediated cell signal regulation in epidermis (5R01AR073858-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9903230. Licensed CC0.

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