# Regulation of Necroptosis and inflammation

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $363,713

## Abstract

Abstract
 The term programmed necrosis or necroptosis has been used to distinguish several types of cell death
such as apoptosis, autophagy, and pyroptosis. Necroptosis has been linked to inflammation response and
diseases, which is a contributing factor for tumor initiation and progression. The protein kinase RIP1 and RIP3
are critical for the activation of necroptosis. Many studies have shown a complex functional interplay between
RIP1 and RIP3 in regulating necrosome formation and necroptosis. Misregulation of this pathway would trigger
abnormal tissue homeostasis, inflammation response, and caner initiation or progression. For example,
abnormal RIP3-induced necroptosis in intestinal epithelium cause inflammatory bowel disease, which is linked
to the development of colorectal cancer. Although RIP3 is a crucial kinase in necroptosis, how RIP3 is
regulated in cells is not clear. We recently found that Parkin regulates RIP3 during necroptosis. Parkin is an
E3 ubiquitin ligase that is encoded by the PARK2 gene. Mutation in the PARK2 gene is the most frequent
cause of autosomal recessive early onset of Parkinson's Disease (PD). Emerging evidence suggests that
Parkin also functions as a tumor suppressor, although how Parkin functions as a tumor suppressor remains
unclear. Recently, we found that Parkin is a negative regulator of necroptosis and inflammation. Parkin
promotes RIP3 ubiquitination, inhibits RIP3 phosphorylation, necrosome formation, and necroptosis in various
cells. Conversely, deletion of the Parkin gene results in increased necroptosis. Importantly, deletion of the
Park2 gene promotes inflammation and hyperplasia in vivo. Interestingly, we also found that Parkin itself is
regulated by AMP-activated protein kinase (AMPK). Based on these preliminary results, we hypothesize that
the AMPK-Parkin pathway is an important negative regulator of RIP3 by promoting RIP3 ubiquitination
and inactivation. Further, the AMPK-Parkin-RIP3 pathway suppresses inflammation-induced
tumorigenesis. To test this hypothesis, we propose the following Specific Aims: 1. To study the role of Parkin
in RIP3 regulation and necroptosis; 2. To study the regulation of Parkin by AMPK; 3. To study the role of
Parkin in inflammation and cancer. These studies will reveal a novel role of Parkin in the regulation of RIP3,
necroptosis, and inflammation. In addition, a new mechanism by which Parkin functions as a tumor
suppressor will be revealed. Accordingly, these studies will have a high impact for cancer pathogenesis and
future cancer prevention.
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## Key facts

- **NIH application ID:** 10070084
- **Project number:** 5R01CA224921-03
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Zhenkun Lou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $363,713
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070084

## Citation

> US National Institutes of Health, RePORTER application 10070084, Regulation of Necroptosis and inflammation (5R01CA224921-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10070084. Licensed CC0.

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