# Novel regulation of the CDK4/Cdh1/Pin1 signaling axis for targeted breast cancer therapies

> **NIH NIH K99** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $169,884

## Abstract

Project Summary/Abstract:
 The anaphase-promoting complex/Cyclosome (APC/C) is a well-defined multi-subunit E3 ubiquitin
ligase that regulates targeted cell cycle regulators for degradation by the Ubiquitin Proteasome Pathway
(UPP), promoting cell cycle progression from metaphase to anaphase and being involved in G1 phase
maintenance. The APC/C E3 ligase complex is evolutionarily conserved and relies on two adaptor proteins,
Cdc20 and Cdh1, to recognize different target proteins and regulate cell cycle progression. However,
compared to Cdc20 that is subjected to Cdh1-mediated destruction, regulation of the E3 ligase activity of
Cdh1 is not well known yet. Previous study has shown that there were 19 serine and threonine residues on
Cdh1 that can be phosphorylated by multi-kinases in vivo, indicating that the phosphoregulation of Cdh1 is
much more complex. In the present proposal, I found that CDK4 can phosphorylates Cdh1 in vitro and
modulates its E3 ligase activity. Furthermore, we found that the phosphorylation of Cdh1 by CDK4 can be
recognized by the Pin1 proline isomerase, facilitating Cdh1-Pin1 complex formation. In keeping with this
notion, employment of the CDK4/6 inhibitor or mutating the phosphorylation sites can disrupt the Cdh1-Pin1
interaction. Consequently, Cdh1 can mediate Pin1 for polyubiquitination and degradation. As such, depletion
of endogenous Cdh1 abolished the Pin1 inhibitor treatment induced Pin1 degradation in cells. Importantly,
the Pin1 inhibitor-induced cell proliferation suppression was also abolished in Cdh1-null MEFs, suggesting
the functional presence of Cdh1 is required for Pin1 inhibitor-induced cell proliferation suppression. In
addition, combination of the CDK4/6 inhibitor and Pin1 inhibitor exhibits significantly enhanced suppressing
effect in breast cancer cells. In the first Aim of this proposal, I am going to explore the role of CDK4 kinase in
regulating the E3 ligase activity of Cdh1 (Aim #1). Therefore, the second Aim in this proposal will be
exploring the potential role of Cdh1 in mediating Pin1 inhibitor treatment induced Pin1 protein destruction
(Aim 2). Together, these results implicate a functional role of the CDK4/Cdh1/Pin1 signaling axis in regulating
cell proliferation, and provide rational for combining the CDK4/6 inhibitor and Pin1 inhibitor to treat breast
cancer.

## Key facts

- **NIH application ID:** 10281417
- **Project number:** 1K99CA263194-01
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Fabin Dang
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $169,884
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10281417

## Citation

> US National Institutes of Health, RePORTER application 10281417, Novel regulation of the CDK4/Cdh1/Pin1 signaling axis for targeted breast cancer therapies (1K99CA263194-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10281417. Licensed CC0.

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