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Studying Proteolysis of Cyclin B at the Single Cell Level in Whole Cell Populations
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APC/C CDH1 ubiquitinates STAT3 in mitosis

Debanjan Bhattacharjee1, Sreeram Kaveti1, Nishant Jain1

  • 1Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, Telangana State, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Sector 19, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India.

The International Journal of Biochemistry & Cell Biology
|November 18, 2022
PubMed

Insights

Targeting STAT3 ubiquitination, not inhibition, shows promise for cancer therapy. Researchers identified APC/C CDH1 as the E3-ligase responsible for STAT3 ubiquitination during mitosis, suggesting a new therapeutic window.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Signal transducer and activator of transcription 3 (STAT3) is an oncogene implicated in tumor growth and poor prognosis.
  • Small molecule STAT3 inhibitors have shown limited clinical success, prompting interest in alternative strategies like STAT3 degraders.
  • STAT3 degraders leverage ubiquitination to elicit long-lasting anti-tumor responses, making STAT3 ubiquitination a more effective therapeutic strategy than inhibition.

Purpose of the Study:

  • To identify E3-ligases responsible for STAT3 ubiquitination in cancer cells.
  • To understand the cell cycle-dependent regulation of STAT3 ubiquitination.
  • To explore the relationship between STAT3 dephosphorylation and ubiquitination for improved cancer therapy design.

Main Methods:

  • Investigated cell cycle-dependent ubiquitination of STAT3 in HEK293T cells.
  • Examined the link between STAT3 dephosphorylation and ubiquitination.
  • Identified the E3-ligase complex responsible for STAT3 ubiquitination during mitosis.

Main Results:

  • STAT3 ubiquitination is significantly higher during mitosis compared to other cell cycle phases.
  • The anaphase-promoting complex/cyclosome (APC/C) with its coactivator CDH1 was identified as the E3-ligase that binds and ubiquitinates STAT3 in mitosis.
  • Inhibition of phosphatases led to decreased STAT3 ubiquitination, suggesting a role for dephosphorylation in regulating this process.

Conclusions:

  • APC/C CDH1 ubiquitinates STAT3 during mitosis.
  • Mitosis represents a potential therapeutic window for targeting STAT3-activated cancers through E3-ligase-mediated degradation.
Keywords:
CDH1MitosisPhosphorylationSTAT3Ubiquitination

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