UBE1L represses PML/RARα by targeting the PML domain for ISG15ylation

Shah, Sameena; Blumen, Steven R.; Pitha-Rowe, Ian; Kitareewan, Sutisak; Freemantle, Sarah J.; Feng, Qing; Dmitrovsky, Ethan

doi:10.1158/1535-7163.mct-07-0515

Cited by 55 publications

(65 citation statements)

References 29 publications

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“…Both ISG15 [36] and USP18 [19] are deregulated in different cancers, consistent with an important functional role for this DUB in homeostasis of growth-regulatory proteins. This view is supported by our prior work that established ISGylation affects stability of key growth-regulatory proteins in acute promyelocytic leukemia (APL) and lung cancer [16, 17, 19, 20]. Improved understanding of the functional roles played by ISGylation should advance our knowledge of protein destabilization pathways that control oncogenesis by precisely regulating intracellular oncoprotein or tumor suppressor proteins.…”

Section: Discussionmentioning

confidence: 82%

The ISG15-specific protease USP18 regulates stability of PTEN

Mustachio

Kawakami

et al. 2016

Oncotarget

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The ubiquitin-like modifier interferon-stimulated gene 15 (ISG15) is implicated in both oncogenic and tumor suppressive programs. Yet, few ISGylation substrates are known and functionally validated in cancer biology. We previously found specific oncoproteins were substrates of ISGylation and were stabilized by the ISG15-specific deubiquitinase (DUB) ubiquitin specific peptidase 18 (USP18). Using reverse-phase protein arrays (RPPAs), this study reports that engineered loss of the DUB USP18 destabilized the tumor suppressor protein phosphatase and tensin homologue (PTEN) in both murine and human lung cancer cell lines. In contrast, engineered gain of USP18 expression in these same lung cancer cell lines stabilized PTEN protein. Using the protein synthesis inhibitor cycloheximide (CHX), USP18 knockdown was shown to destabilize PTEN whereas USP18 overexpression stabilized PTEN protein. Interestingly, repression of USP18 decreased cytoplasmic PTEN relative to nuclear PTEN protein levels. We sought to identify mechanisms engaged in this PTEN protein destabilization using immunoprecipitation assays and found ISG15 directly conjugated with PTEN. To confirm translational relevance of this work, USP18 and PTEN immunohistochemical expression were compared in comprehensive lung cancer arrays. There was a significant (P < 0.0001) positive correlation and association between PTEN and USP18 protein expression profiles in human lung cancers. Taken together, this study identified PTEN as a previously unrecognized substrate of the ISGylation post-translational modification pathway. The deconjugase USP18 serves as a novel regulator of PTEN stability. This indicates inhibition of ISGylation is therapeutically relevant in cancers.

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Section: Discussionmentioning

confidence: 82%

The ISG15-specific protease USP18 regulates stability of PTEN

Mustachio

Kawakami

et al. 2016

Oncotarget

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“…UBE1L has also been suggested to act as a tumor suppressor. Retinoic acid induces UBE1L and subsequent ISGylation of the PML/RARα fusion protein (16,67,68), whose accumulation is a characteristic of acute promyelocytic leukemia. ISGylation of PML/RARα results in its destabilization by proteasome-mediated degradation, thus overcoming oncogenic potential of the fusion protein, although it is unclear whether ISGylation acts in the same way that ubiquitin signals to proteasome.…”

Section: Discussionmentioning

confidence: 99%

Chemosensitivity is controlled by p63 modification with ubiquitin-like protein ISG15

Jeon

Jo²,

Yoo³

et al. 2012

J. Clin. Invest.

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Identification of the cellular mechanisms that mediate cancer cell chemosensitivity is important for developing new cancer treatment strategies. Several chemotherapeutic drugs increase levels of the posttranslational modifier ISG15, which suggests that ISGylation could suppress oncogenesis. However, how ISGylation of specific target proteins controls tumorigenesis is unknown. Here, we identified proteins that are ISGylated in response to chemotherapy. Treatment of a human mammary epithelial cell line with doxorubicin resulted in ISGylation of the p53 family protein p63. An alternative splice variant of p63, ΔNp63α, suppressed the transactivity of other p53 family members, and its expression was abnormally elevated in various human epithelial tumors, suggestive of an oncogenic role for this variant. We showed that ISGylation played an essential role in the downregulation of ΔNp63α. Anticancer drugs, including doxorubicin, induced ΔNp63α ISGylation and caspase-2 activation, leading to cleavage of ISGylated ΔNp63α in the nucleus and subsequent release of its inhibitory domain to the cytoplasm. ISGylation ablated the ability of ΔNp63α to promote anchorageindependent cell growth and tumor formation in vivo as well to suppress the transactivities of proapoptotic p53 family members. These findings establish ISG15 as a tumor suppressor via its conjugation to ΔNp63α and provide a molecular rationale for therapeutic use of doxorubicin against ΔNp63α-mediated cancers.

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“…The pcDNA3-UbcH8 plasmid was obtained from Dr. Robert M. Krug (University of Texas, Austin, TX). His 6 -tagged pcDNA3-ISG15 and pcDNA3-His-UBP43 expression vectors were previously reported (15,21,22). The HA-tagged pRcCMV-cyclin D1 plasmid was provided by Dr. Steven Dowdy (Washington University School of Medicine).…”

Section: Methodsmentioning

confidence: 99%

UBE1L causes lung cancer growth suppression by targeting cyclin D1

Feng¹,

Sekula²,

Guo³

et al. 2008

Molecular Cancer Therapeutics

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UBE1L is the E1-like ubiquitin-activating enzyme for the IFN-stimulated gene, 15-kDa protein (ISG15). The UBE1L-ISG15 pathway was proposed previously to target lung carcinogenesis by inhibiting cyclin D1 expression. This study extends prior work by reporting that UBE1L promotes a complex between ISG15 and cyclin D1 and inhibited cyclin D1 but not other G 1 cyclins. Transfection of the UBE1L-ISG15 deconjugase, ubiquitin-specific protein 18 (UBP43), antagonized UBE1L-dependent inhibition of cyclin D1 and ISG15-cyclin D1 conjugation. A lysineless cyclin D1 species was resistant to these effects. UBE1L transfection reduced cyclin D1 protein but not mRNA expression. Cycloheximide treatment augmented this cyclin D1 protein instability. UBE1L knockdown increased cyclin D1 protein. UBE1L was independently retrovirally transduced into human bronchial epithelial and lung cancer cells. This reduced cyclin D1 expression and clonal cell growth. Treatment with the retinoid X receptor agonist bexarotene induced UBE1L and reduced cyclin D1 immunoblot expression. A proof-of-principle bexarotene clinical trial was independently examined for UBE1L, ISG15, cyclin D1, and Ki-67 immunohistochemical expression profiles in pretreatment versus post-treatment tumor biopsies. Increased UBE1L with reduced cyclin D1 and Ki-67 expression occurred in human lung cancer when a therapeutic bexarotene intratumoral level was achieved. Thus, a mechanism for UBE1L-mediated growth suppression was found by UBE1L-ISG15 preferentially inhibiting cyclin D1. Molecular therapeutic implications are discussed.

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UBE1L represses PML/RARα by targeting the PML domain for ISG15ylation

Abstract: Acute promyelocytic leukemia (APL) is characterized by expression of promyelocytic leukemia (PML

Cited by 55 publications

References 29 publications

The ISG15-specific protease USP18 regulates stability of PTEN

The ISG15-specific protease USP18 regulates stability of PTEN

Chemosensitivity is controlled by p63 modification with ubiquitin-like protein ISG15

UBE1L causes lung cancer growth suppression by targeting cyclin D1

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