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Updated: Oct 2, 2025

Non-Invasive Ultrasound Assessment of Endometrial Cancer Progression in Pax8-Directed Deletion of the Tumor Suppressors Arid1a and Pten in Mice
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Non-phosphorylatable cyclin D1 mutant potentiates endometrial hyperplasia and drives carcinoma with Pten loss

Akihiro Yoshida1,2,3, Polly Phillips-Mason4, Vincenzo Tarallo4

  • 1Department of Dermatology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH, 44106, USA. axy234@case.edu.

Oncogene
|February 25, 2022
PubMed

Insights

A mutation in cyclin D1 (T286A) stabilizes the protein, promoting cell proliferation and tumor development. This cyclin D1 mutant activates inflammation and NF-κB signaling, driving cancer progression.

Area of Science:

  • Molecular Biology
  • Cell Cycle Regulation
  • Oncology

Background:

  • Cyclin D1-Cyclin Dependent Kinases 4 and 6 (CDK4/6) complex regulates cell cycle progression.
  • Dysregulation of cyclin D1-CDK4/6 contributes to uncontrolled cell proliferation and tumor formation.
  • Phosphorylation at threonine 286 (T286) targets cyclin D1 for degradation; mutations preventing this stabilize the protein.

Purpose of the Study:

  • To investigate the in vivo role of a non-phosphorylatable cyclin D1 mutant (T286A) using a conditional knock-in mouse model.
  • To elucidate the mechanisms by which cyclin D1 T286A contributes to tumor development and progression.

Main Methods:

  • Generated a conditional knock-in mouse model expressing cyclin D1T286A under its endogenous promoter via Cre-lox system.
  • Administered tamoxifen to induce Cre recombinase and activate cyclin D1T286A expression.
  • Analyzed tissue-specific effects in the intestine, uterus, and endometrium, including cooperation with Pten loss.

Main Results:

  • Acute cyclin D1T286A expression induced inflammation, lymphocyte abnormalities, and mesenteric tumors.
  • Tissue-specific expression in the uterus/endometrium, combined with Pten loss, led to endometrial hyperplasia and cancer.
  • Mechanistically, cyclin D1T286A activated NF-κB signaling and augmented inflammation.

Conclusions:

  • Mutation of cyclin D1 at T286 stabilizes the protein, promoting genomic instability and tumor development.
  • Cyclin D1 T286A plays a critical role in regulating inflammation and driving tumorigenesis.
  • The findings highlight the oncogenic potential of stabilized cyclin D1 mutants in cancer.

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