# Regulation of hypoxic response by HIF isomerization

> **NIH NIH R03** · UNIVERSITY OF MINNESOTA · 2020 · $77,000

## Abstract

Project Summary
When a tumor becomes large, hypovascularized and hypoxic regions are formed inside the tumor. The cancer
cells in the regions become resistant to therapy due to poor delivery of chemotherapy drugs and a lack of reactive
oxygen species after irradiation. In addition, the cancer cells upregulate transcription factors of the hypoxia-
inducible factor (HIF) family as master regulators of their response to hypoxia. The HIF-1 protein, one of the
best characterized HIF subunits, is stabilized by hypoxia and forms a dimer with HIF-1 to activate more than
2,500 genes. The target genes are involved in angiogenesis, glycolysis, and growth factor signaling, which
collectively facilitate cancer progression and metastasis. Indeed, increased levels of HIF indicate a poor
prognosis for cancer patients. Thus, it is important to understand the functions and regulation of HIFs to improve
cancer therapy. The principal investigator’s group recently found that some peptide bonds preceding prolines
are cis-trans isomerized by one of the FKBP family of peptidyl prolyl isomerases. This isomerization stabilizes
HIF-1 by preventing ubiquitin-mediated degradation. Based on these findings, the group hypothesized that the
isomerization inhibits HIF-1 phosphorylation of serine or threonine near the prolines that is mediated by GSK3,
which is a major step for degradation. To test this hypothesis, they proposed the following three aims. In Aim 1,
they will use in vitro peptide assays and cell transfection assays to study how isomerization regulates
phosphorylation. In Aim 2, cell biological consequences of FKBP depletion and HIF-1 depletion will be
compared. This includes cell proliferation assays, PCR of HIF-target genes, cell migration assays, and
angiogenesis assays. In Aim 3, transcription activation of the FKBP by HIF-1 will be studied with ChIP-seq,
luciferase reporter assays and electrophoretic mobility shift assays. This aim will determine a positive feedback
loop between FKBP and HIF-1. These studies are expected to unravel a novel molecular mechanism regulating
HIF-1 stability in hypoxia and potential drug targets for cancer therapy.

## Key facts

- **NIH application ID:** 9965874
- **Project number:** 5R03CA241879-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Nobuaki Kikyo
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $77,000
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965874

## Citation

> US National Institutes of Health, RePORTER application 9965874, Regulation of hypoxic response by HIF isomerization (5R03CA241879-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9965874. Licensed CC0.

---

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