# Molecular Basis for Regulation of Cellular Stress Response Pathways by CBP/p300

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $482,214

## Abstract

The transcriptional coactivators CREB binding protein (CBP) and p300 regulate numerous signal
transduction pathways in eukaryotic cells by activation or repression of gene expression. They are
essential for such basic cellular functions as growth, differentiation, apoptosis, DNA repair, and
embryonic development. They also function as tumor suppressors and regulate key genes that control
cellular proliferation, tumorigenesis, and cancer progression. CBP and p300 mediate crosstalk between
many signaling pathways that regulate the response to cellular stress, thereby playing a key role in cell
fate decisions – determining whether cells should survive and proliferate or undergo apoptosis. CBP and
p300 are central hubs in the signaling circuitry of the cell; the amount of CBP/p300 in the cell is limiting
and regulatory proteins must compete for binding. CBP and p300 are absolutely required for activation
of the tumor suppressor p53 and regulation of p53-mediated stress response pathways. They also
perform an indispensable function in the response to hypoxia, by activating transcription of oxygen stress
genes controlled by the hypoxia inducible transcription factor HIF-1α and by acting as a central hub in a
negative feedback circuit in which the protein CITED2 downregulates HIF-1α transactivation by
competition for the TAZ1 domain of CBP/p300. The overarching goals of the present proposal are to
elucidate the structural and molecular basis by which CBP and p300 perform their central regulatory roles
to control the hypoxic response and to protect against oncogenic transformation. Preliminary data show
that the CBP/p300 TAZ1 domain and the activation domains of HIF-1α and CITED2 function
cooperatively to create a unidirectional hypersensitive molecular switch that efficiently displaces the HIF-
1α activation domain from CBP/p300 to downregulate transcription of HIF-1α responsive genes. The
intermolecular interactions that drive this switch will be investigated using affinity measurements and
stopped flow kinetics, and the structural and dynamic features of the system will be characterized by
NMR to provide insights into the detailed molecular mechanism by which this hypersensitive allosteric
switch functions. Switch-like behavior has also been observed in competition between the p65 subunit of
NFκB and HIF-1α, and between p53 and p65 for binding to TAZ1. Biophysical measurements will be
performed to determine the mechanism of p65, p53, and HIF-1α competition. Given the central role of
CBP/p300 as concentration-limited hubs in critical cellular signaling networks, it is likely that allostery
may be a general mechanism by which disordered signaling proteins compete for their targets.

## Key facts

- **NIH application ID:** 10172869
- **Project number:** 5R01CA229652-04
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** PETER Edwin WRIGHT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $482,214
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10172869

## Citation

> US National Institutes of Health, RePORTER application 10172869, Molecular Basis for Regulation of Cellular Stress Response Pathways by CBP/p300 (5R01CA229652-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10172869. Licensed CC0.

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