# The Role of Ribosomal Proteins in the P53-MDM2 Pathway

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2021 · $285,950

## Abstract

Project Summary
The past half a decade has witnessed a great progress in the rapidly growing field of ribosomal stress (RS)-, or
nucleolar stress (NuS)-RP-MDM2-p53 field. Growing evidence has demonstrated the biological importance of
the RS-RP-MDM2-p53 pathway in development of human cancer and genetic diseases, such as 5q syndrome
and Diamond Blackfan anemia (DBA). Also, more ribosomal proteins and their nucleolar or nucleoplasmic
regulators have been identified in modifying this pathway. The crystal structure of the RPL11-MDM2 complex
was just reported, which validated our previous study on the RPL11-MDM2 complex and also offered structural
information for better understanding of the underlying mechanisms. Additional studies have shown that the RS
responsive p53 activation also involves inhibition of MDMX, an MDM2 analog and partner. While trying to
purify our previously proposed sub-ribosome complex that regulates this MDM2-p53 pathway, we identified
Spin1 (Spindlin1) and RPL22 as two new regulators of this pathway. Spin 1 is a nucleolar protein that belongs
to the tudar family, acts as a histone code “reader” to stimulate rRNA expression, and promotes genomic
instability and cell transformation as a potential oncogenic protein. Interestingly, we showed that Spin1 binds to
RPL5, preventing its association with MDM2 and consequently activating MDM2 and inactivating p53.
Identification of RPL22 as another regulator is also remarkably significant because 1) knockout of its gene in
mice is not lethal and non-essential for ribosome assembly and protein translation, and 2) it is highly mutated
human cancers, such as colorectal and endometrial tumors, and/or down-regulated in lung cancer. Since
RPL22 is the first RP whose mutations are highly associated with human cancer, our preliminary findings
highly suggest that this ribosomal protein might be crucially important for preventing tumorigenesis via the RS-
p53 pathway. More interestingly, RPL22 can bind to EBER-1, a short RNA encoded by Epstein-Bar virus (EBV)
highly associated with nasopharyngeal and gastric cancers. Therefore, in light of growing evidence recently
published in literature as well as our own published and preliminary studies, I hypothesize that the RS-RP-
MDM2-p53 pathway is highly regulated by endogenous, such as Spin1, and exogenous, such as EBER-1,
molecules, and this regulation is relevant to virus- or non-virus-pertinent cancer development. We will test this
hypothesis by addressing four aims: 1) To further characterize the RS-RP-MDM2-p53 pathway biochemically;
2) To determine if dual defects of the MDM2-MDMX-p53 pathways rescues 5q-syndrome in mice; 3) To
determine if Spin1 regulates the RPL5-MDM2 pathway; 4) To determine the role of RPL22 in regulation of the
MDM2-p53 loop and cancer development. We will employ biochemical, biophysical, X-ray structural, molecular
biological, cell biological, and genetic tools as well as recombinant proteins, cell line systems, xenograft,
ort...

## Key facts

- **NIH application ID:** 10070577
- **Project number:** 5R01CA095441-21
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Hua Lu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $285,950
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070577

## Citation

> US National Institutes of Health, RePORTER application 10070577, The Role of Ribosomal Proteins in the P53-MDM2 Pathway (5R01CA095441-21). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10070577. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*