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Related Concept Videos

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...
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In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
DNA Damage Can Stall the Cell Cycle02:36

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Purification of Ubiquitinated p53 Proteins from Mammalian Cells
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ATM activates p53 by regulating MDM2 oligomerization and E3 processivity.

Qian Cheng1, Lihong Chen, Zhenyu Li

  • 1Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA.

The EMBO Journal
|October 10, 2009
PubMed
Summary
This summary is machine-generated.

ATM kinase phosphorylates MDM2, a key E3 ligase, to stabilize p53 after DNA damage. This phosphorylation prevents MDM2 self-assembly, halting p53 degradation and enabling DNA repair responses.

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

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Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • DNA Damage Response

Background:

  • Ionizing irradiation rapidly activates p53, a crucial tumor suppressor, through the ATM kinase.
  • The precise signaling pathway and target responsible for p53 stabilization post-DNA damage remain unclear.

Purpose of the Study:

  • To identify the direct signaling target of ATM kinase in the p53 stabilization pathway.
  • To elucidate the mechanism by which ATM regulates p53 stability.

Main Methods:

  • Investigated the interaction between ATM kinase and MDM2.
  • Utilized phosphorylation site mutagenesis (alanine substitution) to block MDM2 phosphorylation.
  • Assessed p53 and MDM2 ubiquitination and degradation levels via Western blotting and proteasomal assays.

Main Results:

  • ATM kinase directly phosphorylates the ubiquitin E3 ligase MDM2 at multiple sites near its RING domain.
  • Phosphorylation by ATM inhibits MDM2 RING domain oligomerization, which is essential for p53 polyubiquitination and degradation.
  • Blocking MDM2 phosphorylation leads to continuous p53 degradation, even after DNA damage.

Conclusions:

  • ATM controls p53 stability by regulating MDM2 RING domain oligomerization and E3 ligase activity.
  • MDM2 RING domain oligomerization is a critical step in p53 ubiquitination and degradation.
  • Modulating E3 ligase oligomerization represents a potential therapeutic strategy for cancer treatment.