Related Experiment Video

Updated: Feb 5, 2026

Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

10.1K

CDK4 inhibition diminishes p53 activation by MDM2 antagonists

Anusha Sriraman1, Antje Dickmanns1, Zeynab Najafova2

  • 1Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, D-37077, Göttingen, Germany.

Cell Death & Disease
|September 13, 2018
PubMed

Insights

Combining MDM2 and CDK4 inhibitors for sarcoma treatment may be counterproductive. CDK4 inhibition unexpectedly reduces the p53 response, hindering MDM2 inhibitor effectiveness and revealing a new role for CDK4 in p53 regulation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • MDM2 and CDK4 genes are often co-amplified in sarcomas.
  • Inhibitors targeting MDM2 and CDK4 are in clinical development for cancer therapy.

Purpose of the Study:

  • To investigate the combined effects of MDM2 and CDK4 inhibition on sarcoma cells.
  • To elucidate the molecular mechanisms underlying the interaction between MDM2 and CDK4 pathways.

Main Methods:

  • Utilized siRNA to co-deplete MDM2 and CDK4.
  • Assessed p53-responsive gene induction and p53 binding.
  • Analyzed the recruitment of RNA Polymerase II to gene promoters.

Main Results:

  • MDM2 and CDK4 inhibitors showed antagonistic cytotoxicity in sarcoma cells.
  • CDK4 inhibition attenuated p53-responsive gene induction and p53 response upon MDM2 inhibition.
  • CDK4 inhibition reduced RNA Polymerase II recruitment, not p53 binding or histone acetylation.

Conclusions:

  • Combined CDK4 and MDM2 inhibition requires careful consideration for sarcoma patient treatment.
  • CDK4 and Cyclin D1 play a previously unrecognized role in maintaining p53 activity.
  • Direct physical association between p53/MDM2 and CDK4/Cyclin D1 complexes suggests cross-regulation.

More Related Videos

Purification of Ubiquitinated p53 Proteins from Mammalian Cells10:55

Purification of Ubiquitinated p53 Proteins from Mammalian Cells

Published on: March 21, 2022

2.8K
NMR-Based Activity Assays for Determining Compound Inhibition, IC50 Values, Artifactual Activity, and Whole-Cell Activity of Nucleoside Ribohydrolases10:24

NMR-Based Activity Assays for Determining Compound Inhibition, IC50 Values, Artifactual Activity, and Whole-Cell Activity of Nucleoside Ribohydrolases

Published on: June 30, 2019

10.6K

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...
6.0K
Cholinergic Antagonists: Chemistry and Structure-Activity Relationship01:29

Cholinergic Antagonists: Chemistry and Structure-Activity Relationship

Cholinergic antagonists bind to cholinergic receptors and limit the effects of acetylcholine and other cholinergic agonists. Based on the specific cholinergic receptor affinity, these antagonists are classified as muscarinic or nicotinic. Anticholinergics interrupt parasympathetic innervations while sympathetic innervations remain uninterrupted. Muscarinic antagonists are also called 'muscarinic antagonists', 'antimuscarinics', or 'parasympatholytics'. Nicotinic...
2.8K
Feedback Inhibition00:46

Feedback Inhibition

Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
57.2K
Cholinergic Antagonists: Pharmacokinetics01:24

Cholinergic Antagonists: Pharmacokinetics

Cholinergic antagonists—such as antimuscarinics—are available in oral, topical, ocular, parenteral, and inhalational formulations. Most antimuscarinics are oral formulations,  while scopolamine is available as a topical patch, and ipratropium and tiotropium are available as inhalation aerosols or powders. Atropine, tropicamide, and cyclopentolate are topically instilled in the eye. Most antimuscarinics are lipid-soluble and readily absorbed from the gastrointestinal tract and...
973
Cholinergic Antagonists: Therapeutic Uses01:26

Cholinergic Antagonists: Therapeutic Uses

Antimuscarinic drugs have various therapeutic applications by inhibiting parasympathetic stimulation in different systems. Here are the key therapeutic uses of antimuscarinics:    
Respiratory Tract: Ipratropium, aclidinium, and tiotropium treat asthma, chronic bronchitis, and chronic obstructive pulmonary disease (COPD). They protect against bronchoconstriction caused by irritants like cigarette smoke, sulfur dioxide, and ozone. They also help reduce nasopharyngeal...
1.5K
Enzyme Inhibition01:30

Enzyme Inhibition

Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
92.5K