# Mechanisms of Epidermal Homeostasis and Early Neoplasia

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $523,510

## Abstract

MECHANISMS OF EPIDERMAL HOMEOSTASIS
 PROJECT SUMMARY
 Biomolecular cues that mediate homeostasis are not fully elucidated. During the most recent
funding cycle, AR043799 found that intracellular glucose increases during differentiation of diverse
cell types where it controls multimerization of nucleic acid binding proteins, independent of its role in
energetics. This new role for glucose is analogous to action as a second messenger. In epidermis,
glucose directly bound specific RNA binding proteins (RBPs), including DDX21, as well as specific
DNA binding protein (DBP) transcription factors (TFs), including IRF6, to alter their dimerization in
ways essential for differentiation. To understand principles of glucose action in homeostasis, this
competing renewal will define the function of glucose binding to additional RBPs and TFs.
 For RBPs, we found that DEAD-box DDX RBPs were among the most enriched glucose binding
proteins essential for epidermal differentiation. Glucose binding dissociated DDX21 dimers,
propelling DDX21 monomers out of the nucleolar rRNA production machinery into nuclear
complexes controlling splicing of essential pro-differentiation mRNAs. In contrast, glucose binding
altered DDX50 association with an entirely different set of interactors and had no effect on RNA
splicing, indicating that glucose binding engages a diversity of pro-differentiation mechanisms for
specific DDX RBPs. Aim I will characterize glucose-enabled DDX50 pro-differentiation functions as
well as the impacts of glucose binding on the subcellular localization, protein interactions, RNA
interactions, mRNA splicing, and RNA-dependent protein assemblies of 3 other glucose-binding
RNA helicases essential for epidermal homeostasis, namely DDX1, DDX17, and DDX18.
 For TFs, we found that glucose binding to IRF6 – in contrast to its dissociating effects on both
DDX21 and DDX50 RBP dimers - induced IRF6 homodimerization, along with IRF6 DNA binding,
genomic targeting, and differentiation gene transcription. This raised the question as to how glucose
impacts other glucose-binding TFs essential for epidermal homeostasis. Among the latter is the pro-
differentiation TF, TFAP2A, which binds DNA as a dimer with other AP-2 subunits. Aim II will
characterize the effects of glucose binding on TFAP2A dimerization and target gene induction.
Epidermal differentiation is enabled by other known factors, including calcium, specific adhesion
proteins, and dominant differentiation-driving TFs. Aim II will therefore also determine the interplay
between physiologic elevation of intracellular glucose and differentiation enabled by representative
important contextual factors in epidermal cells.
 This effort will define the function of glucose-binding regulators in epidermal differentiation to
expand insight into the mechanistic actions of newly identified biomolecular cues in homeostasis.

## Key facts

- **NIH application ID:** 10980200
- **Project number:** 2R01AR043799-26A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** PAUL KHAVARI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $523,510
- **Award type:** 2
- **Project period:** 1996-08-05 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980200

## Citation

> US National Institutes of Health, RePORTER application 10980200, Mechanisms of Epidermal Homeostasis and Early Neoplasia (2R01AR043799-26A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10980200. Licensed CC0.

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