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Related Concept Videos

Anaphase Promoting Complex00:50

Anaphase Promoting Complex

The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
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It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
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The Proteasome01:13

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The destabilization of microtubules can occur during different stages of the microtubule lifecycle, such as nucleation or elongation. It can take place at either end of the microtubule or in the microtubule lattices as a whole. The lifespan of individual microtubules within a cell varies according to the cell type and stage of the cell cycle. During interphase, the lifespan of the microtubule is about 30 minutes, while during cell division, it is about 15 minutes. In axonal microtubules of...
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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.
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Updated: Jul 7, 2026

In Vitro Analysis of E3 Ubiquitin Ligase Function
06:06

In Vitro Analysis of E3 Ubiquitin Ligase Function

Published on: May 14, 2021

Small molecules destabilize cIAP1 by activating auto-ubiquitylation.

Keiko Sekine1, Kohei Takubo, Ryo Kikuchi

  • 1Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan.

The Journal of Biological Chemistry
|January 31, 2008
PubMed
Summary

A novel small molecule, ME-BS, selectively targets and degrades the anti-apoptotic protein cIAP1. This targeted destabilization sensitizes cancer cells to apoptosis, offering a new therapeutic strategy for cIAP1-expressing cancers.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Overexpression of cellular inhibitor of apoptosis protein 1 (cIAP1) is linked to cancer progression and treatment resistance.
  • Genetic amplification of cIAP1 contributes to its overexpression in various cancers, including liver, esophageal, cervical, and lung cancers.
  • cIAP1's anti-apoptotic function promotes tumor survival and hinders the efficacy of chemotherapy and radiotherapy.

Purpose of the Study:

  • To identify and characterize small molecules that selectively target and down-regulate cIAP1.
  • To investigate the mechanism by which ME-BS affects cIAP1 expression and function.
  • To evaluate the therapeutic potential of targeting cIAP1 for cancer treatment.

Main Methods:

  • Screening of small molecules for cIAP1 inhibitory activity.
  • Biochemical assays to determine the interaction of ME-BS with cIAP1.
  • Analysis of ubiquitylation and proteasomal degradation pathways.
  • Assessment of cancer cell apoptosis and chemosensitization in response to ME-BS.

Main Results:

  • (-)-N-[(2S,3R)-3-amino-2-hydroxy-4-phenyl-butyryl]-l-leucine methyl ester (ME-BS) selectively down-regulates cIAP1.
  • ME-BS binds to the BIR3 domain of cIAP1, inducing auto-ubiquitylation via its RING domain.
  • ME-BS promotes proteasomal degradation of cIAP1, sensitizing cancer cells to apoptosis.
  • XIAP and cIAP2 levels remain unaffected by ME-BS treatment.

Conclusions:

  • Targeted destabilization of cIAP1 using small molecules like ME-BS represents a novel therapeutic approach for cancers overexpressing cIAP1.
  • ME-BS demonstrates selective inhibition of cIAP1, leading to enhanced cancer cell apoptosis and potential sensitization to existing therapies.
  • Modulating the intrinsic ubiquitin-ligase activity of cIAP1 is a promising strategy for developing new anti-cancer therapeutics.