Related Experiment Video

Updated: Aug 16, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

Retinoid targeting of different D-type cyclins through distinct chemopreventive mechanisms

Yan Ma1, Qing Feng, David Sekula

  • 1Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.

Cancer Research
|July 19, 2005
PubMed

Insights

All-trans-retinoic acid differentially regulates D-type cyclins (cyclin D1, D2, D3) in human bronchial epithelial cells. This study identifies distinct mechanisms for cyclin D1 and D3 repression, highlighting their potential as cancer chemoprevention targets.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • D-type cyclins (cyclins D1, D2, D3) are crucial for cell cycle progression (G1-S phase) and are frequently dysregulated in various cancers.
  • Previous research indicated all-trans-retinoic acid (ATRA) chemo-prevents carcinogenic transformation by degrading cyclin D1 via proteasomes in human bronchial epithelial (HBE) cells.

Purpose of the Study:

  • To investigate the distinct mechanisms by which ATRA regulates different D-type cyclins (D1, D2, D3) in HBE cells.
  • To elucidate the roles of specific molecular pathways, including proteasomal degradation and glycogen synthase kinase 3 (GSK3), in ATRA's regulation of D-type cyclins.
  • To assess the impact of D-type cyclins on HBE cell growth and their relevance in ATRA response and resistance.

Main Methods:

  • Quantitative analysis of cyclin D1, D2, and D3 mRNA and protein expression following ATRA treatment.
  • Assessment of proteasomal degradation pathways using proteasome inhibitors.
  • Site-directed mutagenesis to investigate the role of specific threonine residues (T286 in cyclin D1, T283 in cyclin D3) in protein stability.
  • Pharmacological inhibition of GSK3 using lithium chloride and SB216763.
  • Gene silencing using small interfering RNAs (siRNAs) to target individual D-type cyclins.
  • Analysis of D-type cyclin expression in ATRA-resistant HBE cells.

Main Results:

  • ATRA differentially affected D-type cyclins: increased cyclin D2 mRNA, decreased cyclin D3 mRNA and protein, and decreased cyclin D1 protein without altering mRNA levels.
  • Early repression of cyclin D3 protein by ATRA was dependent on proteasomal degradation.
  • While T286 mutation stabilized cyclin D1, a homologous mutation in cyclin D3 (T283) did not affect its stability upon ATRA treatment.
  • GSK3 inhibitors (lithium chloride, SB216763) blocked ATRA-induced repression of cyclin D1 protein but not cyclin D3 protein, implicating GSK3 in cyclin D1 regulation.
  • Deregulated expression of cyclins D1 and D3 was observed in ATRA-resistant HBE cells.
  • Individual and combined repression of D-type cyclins using siRNAs significantly suppressed HBE cell growth.

Conclusions:

  • ATRA employs distinct mechanisms to repress cyclin D1 and cyclin D3 protein levels in HBE cells.
  • GSK3 is critically involved in the retinoid-mediated regulation of cyclin D1 stability.
  • D-type cyclins are essential for HBE cell proliferation and represent key molecular targets for cancer chemoprevention strategies involving retinoids.

More Related Videos

Quantitative Analysis of Dietary Vitamin A Metabolites in Murine Ocular and Non-Ocular Tissues Using High-Performance Liquid Chromatography05:03

Quantitative Analysis of Dietary Vitamin A Metabolites in Murine Ocular and Non-Ocular Tissues Using High-Performance Liquid Chromatography

Published on: December 27, 2024

Related Concept Videos

Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Inhibition of CDK Activity02:34

Inhibition of CDK Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
M-Cdk Drives Transition Into Mitosis02:15

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
Positive Regulator Molecules02:39

Positive Regulator Molecules

Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
Positive Regulator Molecules01:45

Positive Regulator Molecules

To consistently produce healthy cells, the cell cycle—the process that generates daughter cells—must be precisely regulated.
The Retinoblastoma Gene01:20

The Retinoblastoma Gene

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...