# Project 1- Micro-RNA-dependent signaling by the UPR

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $291,676

## Abstract

Abstract
Rapidly proliferating cancer cells must thrive in a microenvironment wherein metabolic nutrients such as
glucose, oxygen and growth factors become limiting as tumor volume expands beyond the established
vascularity of the tissue. In normal cells, limits in nutrient availability trigger growth arrest and/or apoptosis
thereby preventing cellular expansion under such conditions. Our scientific premise is that the pro-survival
activities of PERK reflect the combined impact of PERK-dependent differential control of protein synthesis
and gene expression. In the previous funding cycle, we identified miR-211 and miR-216b as a PERK-ATF4
regulated micro-RNAs that regulate cell survival. We identified three critically important miR-211 targets.
The first is the pro-apoptotic transcription factor, Chop. The second target is the Bmal1-Clock heterodimeric
transcription factor that functions as the primary driver of circadian gene expression and thus circadian
oscillation. Both Bmal1 and Clock are direct targets of miR-211 and are repressed by miR-211 during a
UPR. Through analysis of PERK-miR-211 regulation of Bmal1 and the circadian clock, we discovered that
1) circadian gene expression is disrupted by the UPR, 2) Bmal1 loss contributes to PERK-dependent
regulation of mRNA translation. We propose a hypothesis wherein the UPR inducible micro-RNAs (miR-
211, miR-217) regulate cell fate by silencing key targets such as Bmal1 which thereby contributes to PERK-
dependent translational regulation and cell survival. To address this hypothesis, we propose three specific
aims. Aim 1, will defined the critical targets of PERK-miR211-Bmal1 regulation and their contribution to cell
survival. Aim 2 will define the role of miR-217 in antagonizing miR-211 regulation of its transcriptional
targets. Aim 3 will define the role of miR-211-dependent regulation of Bmal1 to the development and
progression of B-cell lymphoma. There are obvious points of cross-talk between this proposal and Project 2
which focuses on how the UPR antagonizes myc induced apoptosis and ATF4-dependent regulation of
tumor cell metabolism. Through collaboration with Project 2, we will assess the role of miR-211 and Bmal1
as a mediator of tumor cell metabolism and survival. Through collaboration with Project 3, we will
determine how miR-211, miR-217 and Bmal1 regulate IFNAR1 signaling and regulation in cytotic T-
lymphocytes. The findings steming from work proposed herein will provide a foundation for the design of
novel anti-cancer therpeutics.

## Key facts

- **NIH application ID:** 10247660
- **Project number:** 5P01CA165997-08
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** John Alan Diehl
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $291,676
- **Award type:** 5
- **Project period:** 2013-09-18 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247660

## Citation

> US National Institutes of Health, RePORTER application 10247660, Project 1- Micro-RNA-dependent signaling by the UPR (5P01CA165997-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247660. Licensed CC0.

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