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Related Concept Videos

The Proteasome01:13

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin...
The Proteasome02:18

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
The Proteasome02:18

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
The Proteasome Structure01:17

The Proteasome Structure

The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
The proteasome is an...
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...

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Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
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Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

Published on: October 23, 2019

Proteasome proteolytic profile is linked to Bcr-Abl expression.

Lisa J Crawford1, Phlip Windrum, Laura Magill

  • 1Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.

Experimental Hematology
|January 23, 2009
PubMed
Summary

Chronic myeloid leukemia (CML) involves higher proteasome activity linked to Bcr-Abl expression. Targeting the proteasome offers a new therapeutic strategy for CML, especially for imatinib-resistant cases.

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Area of Science:

  • Biochemistry
  • Oncology
  • Molecular Biology

Background:

  • Proteasome activity is elevated in chronic myeloid leukemia (CML) bone marrow compared to normal controls.
  • The role of Bcr-Abl expression in this increased proteasome activity remains to be fully elucidated.

Purpose of the Study:

  • To investigate the relationship between Bcr-Abl expression and proteasome activity in CML.
  • To assess the therapeutic potential of proteasome inhibition in CML, including imatinib-resistant cases.

Main Methods:

  • Proteasome activity was profiled using fluorogenic substrate assays and activity-based probes in CML cell lines.
  • The effects of the proteasome inhibitor BzLLLCOCHO were evaluated on CML cell lines and primary CML cells.
  • Small interfering RNA (siRNA) targeting Bcr-Abl was used to assess its impact on proteasome activity.

Main Results:

  • Oncogenic transformation by BCR-ABL directly correlates with increased proteasome proteolytic activity.
  • Bcr-Abl knockdown using siRNA significantly reduces proteasome activity.
  • Bcr-Abl-positive CML cells exhibit increased sensitivity to apoptosis induced by the proteasome inhibitor BzLLLCOCHO.
  • Combined treatment with imatinib and BzLLLCOCHO shows an additive apoptotic effect in Bcr-Abl-positive cells.
  • CML cell lines resistant to imatinib remain sensitive to proteasome inhibition.

Conclusions:

  • A direct link between BCR-ABL transformation and proteasome enzymatic activity has been established.
  • The proteasome represents a promising therapeutic target in CML treatment.
  • Proteasome inhibition may be particularly effective for CML patients resistant to conventional therapies like imatinib.