Related Experiment Video

Updated: Aug 13, 2026

Profiling Ubiquitin and Ubiquitin-like Dependent Post-translational Modifications and Identification of Significant Alterations
10:26

Profiling Ubiquitin and Ubiquitin-like Dependent Post-translational Modifications and Identification of Significant Alterations

Published on: November 7, 2019

Elevated expression of ISG15 in tumor cells interferes with the ubiquitin/26S proteasome pathway

Shyamal D Desai1, Arthur L Haas, Laurence M Wood

  • 1Department of Pharmacology, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA.

Cancer Research
|January 21, 2006
PubMed

Insights

Interferon-stimulatory gene factor 15 (ISG15) protein levels increase in tumors, negatively impacting protein degradation. ISG15 knockdown restores polyubiquitinated protein levels, suggesting a role in regulating the ubiquitin-proteasome pathway.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Interferon-stimulatory gene factor 15 (ISG15) is a ubiquitin-like modifier with an unclear role in protein degradation.
  • ISG15 conjugation to cellular proteins is observed, but its specific function remains elusive.

Purpose of the Study:

  • To investigate the role of ISG15 in protein degradation, particularly in the context of cancer.
  • To determine the relationship between ISG15 levels and the ubiquitin-proteasome system in tumor cells.

Main Methods:

  • Quantitative analysis of ISG15 and polyubiquitinated proteins in tumor samples and cell lines.
  • ISG15 knockdown using small interfering RNA (siRNA).
  • Knockdown of UbcH8, a key E2 enzyme for ISG15 conjugation.

Main Results:

  • ISG15 is significantly elevated and conjugated to proteins in various tumors and cancer cell lines.
  • Elevated ISG15 levels correlate with decreased polyubiquitinated protein levels in tumors.
  • ISG15 or UbcH8 knockdown leads to an increase in polyubiquitinated proteins, indicating ISG15 antagonizes ubiquitin-mediated protein turnover.

Conclusions:

  • The ISG15 pathway is deregulated during tumorigenesis.
  • ISG15 negatively regulates the ubiquitin/proteasome pathway by interfering with protein polyubiquitination and degradation.
  • Targeting the ISG15 pathway may offer novel therapeutic strategies for cancer by modulating protein turnover.

More Related Videos

Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates09:47

Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates

Published on: May 10, 2022

Comparative Strategies for Ubiquitination Detection in Mammalian Cell Lysates Using SMAD2/SMURF2 as a Model09:00

Comparative Strategies for Ubiquitination Detection in Mammalian Cell Lysates Using SMAD2/SMURF2 as a Model

Published on: April 17, 2026

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...
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...
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR activation may...
Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...