Several noncontiguous domains of CDK4 are involved in binding to the P16 tumor suppressor protein

Related Experiment Video

Updated: Oct 28, 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

H M Ceha1, I Nasser, R H Medema

  • 1Department of Radiotherapy, Academic Medical Center, Amsterdam, The Netherlands.

Biochemical and Biophysical Research Communications
|August 26, 1998
PubMed

Insights

Mutations in cyclin-dependent kinase 4 (CDK4) can disrupt its binding to the tumor suppressor p16, potentially driving cancer. This study identified new CDK4 sites critical for p16 interaction, suggesting novel oncogenic mechanisms.

Area of Science:

  • Molecular Biology
  • Cancer Genetics
  • Cell Cycle Regulation

Background:

  • Cyclin-dependent kinase 4 (CDK4) regulates cell cycle progression.
  • CDK4 activity is inhibited by the tumor suppressor p16, which is frequently altered in cancers.
  • A known mutation at CDK4 codon 24 disrupts p16 binding, creating a dominant oncogene found in melanoma.

Purpose of the Study:

  • To identify novel sites on CDK4 involved in p16 binding.
  • To investigate the impact of various CDK4 mutations on p16 interaction.
  • To understand the oncogenic potential of CDK4 variants with impaired p16 binding.

Main Methods:

  • Charged-to-Alanine scanning mutagenesis was used to generate 18 CDK4 mutants.
  • Mutant CDK4 proteins were produced using in vitro coupled transcription-translation.
  • p16-binding capacity was assessed using a p16-GST fusion protein assay.

Main Results:

  • Several CDK4 mutants exhibited a loss of p16 binding.
  • Mutations at codons 22, 25, 97, and 281, in addition to codon 24, impaired p16 binding.
  • These findings indicate that multiple, non-contiguous regions of CDK4 are essential for p16 interaction.

Conclusions:

  • CDK4 binding to p16 involves several distinct amino acid sequences.
  • Impaired p16 binding to CDK4 suggests multiple interaction sites.
  • These p16-binding deficient CDK4 mutations may contribute to the development of melanoma and other cancers.

More Related Videos

Analysis of Cell Cycle Position in Mammalian Cells12:19

Analysis of Cell Cycle Position in Mammalian Cells

Published on: January 21, 2012

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...
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.
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
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...
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...