ISG15: a ubiquitin-like enigma

Dao, Chinh T.; Zhang, Dong‐Er

doi:10.2741/1730

Cited by 105 publications

(104 citation statements)

References 180 publications

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“…Because type I IFN are known to induce the ISG15 pathway (22,23,26), a combined use of type I IFN and CPT (or other TOP1-targeting drugs) is expected to increase CPT sensitivity in tumors expressing low levels of ISG15. Indeed, IFN have been shown to exhibit synergistic anticancer activity with CPT-11 against human colon cancer xenografts in nude mice (39,40).…”

Section: Discussionmentioning

confidence: 99%

ISG15 as a novel tumor biomarker for drug sensitivity

Desai¹,

Wood²,

Tsai³

et al. 2008

Molecular Cancer Therapeutics

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Tumor cells are known to exhibit highly varied sensitivity to camptothecins (CPT; e.g., irinotecan and topotecan). However, the factors that determine CPT sensitivity/ resistance are largely unknown. Recent studies have shown that the ubiquitin-like protein, IFN-stimulated gene 15 (ISG15), which is highly elevated in many human cancers and tumor cell lines, antagonizes the ubiquitin/ proteasome pathway. In the present study, we show that ISG15 is a determinant for CPT sensitivity/resistance possibly through its effect on proteasome-mediated repair of topoisomerase I (TOP1)-DNA covalent complexes. First, short hairpin RNA-mediated knockdown of either ISG15 or UbcH8 (major E2 for ISG15) in breast cancer ZR-75-1 cells decreased CPT sensitivity, suggesting that ISG15 overexpression in tumors could be a factor affecting intrinsic CPT sensitivity in tumor cells. Second, the level of ISG15 was found to be significantly reduced in several tumor cells selected for resistance to CPT, suggesting that altered ISG15 regulation could be a significant determinant for acquired CPT resistance. Parallel to reduced CPT sensitivity, short hairpin RNAmediated knockdown of either ISG15 or UbcH8 in ZR-75-1 cells resulted in increased proteasomal degradation of CPT-induced TOP1-DNA covalent complexes. Taken together, these results suggest that ISG15, which interferes with proteasome-mediated repair of TOP1-DNA covalent complexes, is a potential tumor biomarker for CPT sensitivity.

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Section: Discussionmentioning

confidence: 99%

ISG15 as a novel tumor biomarker for drug sensitivity

Desai¹,

Wood²,

Tsai³

et al. 2008

Molecular Cancer Therapeutics

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“…ISG15 is a ubiquitin-like small molecule encoded by an interferon (IFN)-stimulated gene. Similar to ubiquitin, it modifies substrate proteins posttranslationally by forming convalent conjugations (ISGylation) [12]. The three sequential reaction steps -activation, conjugation and ligation -are catalyzed by enzyme E1, E2 and E3, respectively.…”

Section: Introductionmentioning

confidence: 99%

Deficiency of a potential 3p21.3 tumor suppressor gene UBE1L (UBA7) does not accelerate lung cancer development in K-rasLA2 mice

et al. 2009

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SummaryGenetic lesions in chromosomal region 3p21.3 marks one of the earliest events in human lung cancer development. It is hypothesized that one or more tumor suppressor genes reside in this region. Identification and characterization of these genes are important for the understanding of lung cancer initiation. UBE1L (UBA7) is a long-suspected 3p21.3 residing tumor suppressor gene. It encodes the key enzyme that activates ISGylation, a novel, ubiquitination-like, post-translational protein modification system that is inducible by interferon. It has been implicated that ISGylation plays a variety of biological roles ranging from viral defense to tumor surveillance. Here we tested the possible function of ISGylation during lung cancer development by using the Ube1l-deficient mice and the K-ras LA2 lung cancer mice. Protein ISGylation levels were largely unchanged during lung cancer progression. Ube1l deficiency neither altered the lung cancer progression nor affected the overall survival of K-ras LA2 lung cancer mice. Our study suggests that Ube1l is not a tumor suppressor gene in K-ras LA2 lung cancer mouse model. However, as described in the discussion, additional studies with other lung cancer mouse models will be necessary to elucidate the potential tumor suppressor function of UBE1L in K-RAS mutation independent human lung cancers.

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“…ISG15 contains two ubiquitin-like domains and belongs to the ubiquitin-like protein family. The expression of ISG15 is induced by interferon stimulation and ISG15 is conjugated to various cellular proteins (ISGylation) in a manner similar to ubiquitination that is catalyzed by the sequential action of E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme) and E3 (ubiquitin ligase) [4,5]. Target proteins modified with ISG15 [6][7][8], the E1 (UBE1L) and E2 (UbcH8) enzymes functioning in ISGylation [9][10][11], and a de-ISGylating enzyme (UBP43) [12] have been identified, but biological consequences of ISGylation have been studied in only a few cases [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Identification and Herc5-mediated ISGylation of novel target proteins

Takeuchi

Inoue

Yokosawa

2006

Biochemical and Biophysical Research Communications

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ISG15, a protein containing two ubiquitin-like domains, is an interferon-stimulated gene product that functions in antiviral response and is conjugated to various cellular proteins (ISGylation) upon interferon stimulation. ISGylation occurs via a pathway similar to the pathway for ubiquitination that requires the sequential action of E1/E2/E3: The E1 (UBE1L), E2 (UbcH8), and E3 (Efp/Herc5) enzymes for ISGylation have been hitherto identified. In this study, we identified six novel candidate target proteins for ISGylation by a proteomic approach. Four candidate target proteins were demonstrated to be ISGylated in UBE1L-and UbcH8-dependent manners, and ISGylation of the respective target proteins was stimulated by Herc5. In addition, Herc5 was capable of binding with the respective target proteins. Thus, these results suggest that Herc5 functions as a general E3 ligase for protein ISGylation.

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ISG15: a ubiquitin-like enigma

Cited by 105 publications

References 180 publications

ISG15 as a novel tumor biomarker for drug sensitivity

ISG15 as a novel tumor biomarker for drug sensitivity

Deficiency of a potential 3p21.3 tumor suppressor gene UBE1L (UBA7) does not accelerate lung cancer development in K-rasLA2 mice

Identification and Herc5-mediated ISGylation of novel target proteins

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