# Molecular basis for regulation of CREB by cell stress and retroviral oncoproteins

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $599,187

## Abstract

Approximately one-third of the proteins in the human proteome are intrinsically disordered (IDPs). IDPs
play a central role in cellular signaling and regulatory pathways and are directly implicated in numerous
devastating diseases such as cancer, leukemia, diabetes, and neurodegenerative disease. Because of
the central role of IDPs in signaling and regulation and the unique features of their complexes with their
physiological partners, interactions involving disordered proteins are frequently targeted by viral proteins
that mimic cellular IDP motifs. Many regulatory IDPs function through the transient assembly of multi-
component signaling complexes, where flexibility and dynamic exchange of binding partners plays a
critical role. The dynamic nature of IDPs and their regulatory complexes imposes a major challenge to
traditional structural biology techniques. The overarching goal of this project is to characterize the
conformational ensemble and interactions of a key intrinsically disordered transcription factor, the cyclic
AMP response element binding protein (CREB), to elucidate the molecular mechanism by which its
activity is down regulated by hyperphosphorylation in response to DNA damage and by binding to an
important human T cell leukemia virus oncoprotein that promotes lymphoid cell transformation and
progression of leukemia. CREB plays a critical role in regulating normal hematopoietic stem cell
differentiation and is implicated in proliferation of myeloid and acute leukemias. Transcription of CREB-
responsive genes is regulated by phosphorylation at multiple sites and by interactions with the CBP/p300
and CRTC coactivators. A powerful combination of complementary biophysical tools - NMR, single
molecule FRET (smFRET), and small angle X-ray scattering (SAXS) – will be used to characterize the
conformation of CREB and conformational changes associated with hyperphosphorylation and with
binding to DNA, coactivators, and the basic leucine zipper oncoprotein (HBZ) of human T-cell leukemia
virus type 1.

## Key facts

- **NIH application ID:** 9830586
- **Project number:** 5R01CA214054-04
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Ashok A Deniz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $599,187
- **Award type:** 5
- **Project period:** 2016-12-05 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830586

## Citation

> US National Institutes of Health, RePORTER application 9830586, Molecular basis for regulation of CREB by cell stress and retroviral oncoproteins (5R01CA214054-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9830586. Licensed CC0.

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