# Control of Protein Synthesis by the UPS Under Stress

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2020 · $407,536

## Abstract

PROJECT SUMMARY
This proposal is based on a newly discovered regulatory arm of the cellular stress response, whereby Jun N-
terminal kinase (JNK) is recruited to translating ribosomes (polysomes) to mediate degradation of newly
synthesized proteins (NSPs). We established the significance of this novel regulatory module to breast cancer
(BCa) biology, and identify ubiquitin proteasome system (UPS) components that—for the first time—are linked
with the surveillance of NSPs. They include Cullin 2, Nedd8, and ubiquilin1 (UBQLN1), which we demonstrate
to impact protein synthesis in BCa cells. Dysregulated expression of these UPS components in BCa underlies
the rationale for studying their role in BCa development and response to therapy.
Our preliminary results support the hypothesis that control of NSP stability constitutes a novel layer of
regulation of protein synthesis/availability, which in turn governs cellular responses to stress. We
further hypothesize that such regulation has direct implications for BCa development and response to
therapy. We focus on several complementary but hitherto unappreciated mechanisms that may underlie NSP
surveillance under stress.
The productive and long-standing collaborations between Drs. Topisirovic, Sonenberg, Mills and Ronai are
now extended to include Dr. Meller, thereby enabling extensive and complementary expertise in the areas of
protein synthesis and cancer biology to also include nanopore-sensing technology, enabling the resolution of
ubiquitin chain topologies. Together, we will assess specific, newly identified NSP regulatory factors that
function individually or in concert to regulate the cellular stress response, particularly in the context of BCa
development and response to therapy. The proposed research will: (1) Establish the physiological
significance of the RACK1–JNK–eEF1A2 regulatory axis to the cellular stress response, growth and
therapeutic response of breast cancer. (2) Assess the role of stress-induced polysomal recruitment of
Nedd8–Cullin machinery in regulating the decay of NSPs in BCa. (3) Determine the importance of
UBQLN1 recruitment to polysomes in regulating newly synthesized proteins under stress conditions
and in modulating the response of BCa to therapy.
Our proposed studies will establish the importance and significance of select UPS components in a novel
regulatory network that controls protein synthesis during cellular stress, and establish its role in BCa using a
combination of BCa cultures and xenografts, RPPA technology, and TCGA dataset mining.

## Key facts

- **NIH application ID:** 9952353
- **Project number:** 5R01CA202021-05
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Zeev A. Ronai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $407,536
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952353

## Citation

> US National Institutes of Health, RePORTER application 9952353, Control of Protein Synthesis by the UPS Under Stress (5R01CA202021-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9952353. Licensed CC0.

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