Common and reversible regulation of wild-type p53 function and of ribosomal biogenesis by protein kinases in human

Related Experiment Video

Updated: Aug 8, 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

T David-Pfeuty1, Y Nouvian-Dooghe, V Sirri

  • 1UMR 146 du CNRS, Institut Curie-Recherche, Bâtiment 110, Centre Universitaire, 91405 Orsay Cédex, France. Thérèse.Pfeuty@curie.u-psud.fr

Oncogene
|October 11, 2001
PubMed

Insights

Cyclin-dependent kinase 2 (Cdk2) inhibitors like roscovitine and DRB cause reversible nucleolar changes and p53 alterations. Prolonged exposure leads to irreversible cell cycle arrest and death, impacting ribosomal biogenesis and cell division.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Specific inhibitors of cyclin-dependent kinase 2 (Cdk2), roscovitine and olomoucine, induce nuclear p53 accumulation and nucleolar unravelling in human cells.
  • Casein kinase II (CKII) inhibitor, 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), also affects cellular processes.
  • The p53-Rb pathway and ribosomal biogenesis are crucial for cell growth and division.

Purpose of the Study:

  • To investigate the reversibility of cellular responses to Cdk2 and CKII inhibitors.
  • To elucidate the role of p21(WAF1/CIP1) in nucleolar function and cell fate.
  • To understand how these kinase inhibitors impact cell cycle progression and ribosomal biogenesis.

Main Methods:

  • Treatment of MCF-7 and IMR-90 cells with roscovitine and DRB.
  • Analysis of nucleolar organization, p53 levels, and p21(WAF1/CIP1) expression.
  • Assessment of 45S precursor ribosomal RNA levels and cell cycle progression.
  • Studies involving constitutive overexpression of p21(WAF1/CIP1).

Main Results:

  • Early exposure (4h) to roscovitine in MCF-7 cells resulted in reversible nucleolar restoration, p21(WAF1/CIP1) induction, p53 downregulation, and cell cycle resumption.
  • Both roscovitine and DRB reversibly reduced 45S precursor ribosomal RNA levels upon short-term treatment.
  • Prolonged treatment with both inhibitors led to irreversible cell cycle arrest and death, with differential effects on p21(WAF1/CIP1) accumulation.
  • Overexpression of p21(WAF1/CIP1) modulated nucleolar unravelling differently in the presence of DRB versus roscovitine.

Conclusions:

  • Cellular responses to Cdk2 and CKII inhibitors can be reversible upon early removal, impacting nucleolar organization, p53 status, and cell cycle.
  • p21(WAF1/CIP1) plays a role in regulating nucleolar function, particularly in response to DRB.
  • Inhibitors targeting Cdk2 and CKII kinases link cell growth control with cell division through their effects on the p53-Rb pathway and ribosomal biogenesis.

More Related Videos

Studying RNA Interactors of Protein Kinase RNA-Activated during the Mammalian Cell Cycle10:05

Studying RNA Interactors of Protein Kinase RNA-Activated during the Mammalian Cell Cycle

Published on: March 5, 2019

Purification of Ubiquitinated p53 Proteins from Mammalian Cells10:55

Purification of Ubiquitinated p53 Proteins from Mammalian Cells

Published on: March 21, 2022

Related Concept Videos

Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.
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...
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...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...