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USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy.

García-Santisteban I, Peters GJ, Giovannetti E, Rodríguez JA - Mol. Cancer (2013)

Bottom Line: Importantly, USP1 expression is deregulated in certain types of human cancer, suggesting that USP1 could represent a valid target in cancer therapy.We also summarize USP1 alterations found in cancer, combining data from the literature and public databases with our own data.Finally, we discuss the emerging potential of USP1 as a target, integrating published data with our novel findings on the effects of the USP1 inhibitor pimozide in combination with cisplatin in NSCLC cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Leioa, Spain.

ABSTRACT
Reversible protein ubiquitination is emerging as a key process for maintaining cell homeostasis, and the enzymes that participate in this process, in particular E3 ubiquitin ligases and deubiquitinases (DUBs), are increasingly being regarded as candidates for drug discovery. Human DUBs are a group of approximately 100 proteins, whose cellular functions and regulatory mechanisms remain, with some exceptions, poorly characterized. One of the best-characterized human DUBs is ubiquitin-specific protease 1 (USP1), which plays an important role in the cellular response to DNA damage. USP1 levels, localization and activity are modulated through several mechanisms, including protein-protein interactions, autocleavage/degradation and phosphorylation, ensuring that USP1 function is carried out in a properly regulated spatio-temporal manner. Importantly, USP1 expression is deregulated in certain types of human cancer, suggesting that USP1 could represent a valid target in cancer therapy. This view has gained recent support with the finding that USP1 inhibition may contribute to revert cisplatin resistance in an in vitro model of non-small cell lung cancer (NSCLC). Here, we describe the current knowledge on the cellular functions and regulatory mechanisms of USP1. We also summarize USP1 alterations found in cancer, combining data from the literature and public databases with our own data. Finally, we discuss the emerging potential of USP1 as a target, integrating published data with our novel findings on the effects of the USP1 inhibitor pimozide in combination with cisplatin in NSCLC cells.

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Regulatory motifs in USP1 amino acid sequence. Schematic representation of USP1 protein showing the position of sequence motifs that contribute to the regulation of its levels, localization and activity. These regulatory motifs include a destruction box or “degron” (orange) that mediates APC/CCdh1-mediated degradation of USP1, and two NLSs (blue) that mediate import of the USP1/UAF1 complex into the nucleus. The UAF1-binding region of USP1 is still a matter of some controversy. As indicated within the box, two different motifs have been proposed [73,74]. The position of the diglycine motif (Gly-Gly), which constitutes the site of USP1 autocleavage, and the residue Ser313, which is the site of Cdk-mediated USP1 phosphorylation, are also indicated.
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Figure 2: Regulatory motifs in USP1 amino acid sequence. Schematic representation of USP1 protein showing the position of sequence motifs that contribute to the regulation of its levels, localization and activity. These regulatory motifs include a destruction box or “degron” (orange) that mediates APC/CCdh1-mediated degradation of USP1, and two NLSs (blue) that mediate import of the USP1/UAF1 complex into the nucleus. The UAF1-binding region of USP1 is still a matter of some controversy. As indicated within the box, two different motifs have been proposed [73,74]. The position of the diglycine motif (Gly-Gly), which constitutes the site of USP1 autocleavage, and the residue Ser313, which is the site of Cdk-mediated USP1 phosphorylation, are also indicated.

Mentions: Transcription of the USP1 gene is regulated in a cell cycle-dependent manner. USP1 mRNA levels remain low during G1 phase, and reach a peak during S phase [55]. The cell cycle-dependent expression of USP1 is also regulated at the protein level by proteasomal degradation. In this regard, the USP1 region 295-342 (Figure 2) constitutes a destruction motif (degron) that is required for Anaphase Promoting Complex/CyclosomeCdh1 (APC/CCdh1)-dependent degradation of USP1 during G1 [71], which appears to be further modulated by calpains [72].


USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy.

García-Santisteban I, Peters GJ, Giovannetti E, Rodríguez JA - Mol. Cancer (2013)

Regulatory motifs in USP1 amino acid sequence. Schematic representation of USP1 protein showing the position of sequence motifs that contribute to the regulation of its levels, localization and activity. These regulatory motifs include a destruction box or “degron” (orange) that mediates APC/CCdh1-mediated degradation of USP1, and two NLSs (blue) that mediate import of the USP1/UAF1 complex into the nucleus. The UAF1-binding region of USP1 is still a matter of some controversy. As indicated within the box, two different motifs have been proposed [73,74]. The position of the diglycine motif (Gly-Gly), which constitutes the site of USP1 autocleavage, and the residue Ser313, which is the site of Cdk-mediated USP1 phosphorylation, are also indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750636&req=5

Figure 2: Regulatory motifs in USP1 amino acid sequence. Schematic representation of USP1 protein showing the position of sequence motifs that contribute to the regulation of its levels, localization and activity. These regulatory motifs include a destruction box or “degron” (orange) that mediates APC/CCdh1-mediated degradation of USP1, and two NLSs (blue) that mediate import of the USP1/UAF1 complex into the nucleus. The UAF1-binding region of USP1 is still a matter of some controversy. As indicated within the box, two different motifs have been proposed [73,74]. The position of the diglycine motif (Gly-Gly), which constitutes the site of USP1 autocleavage, and the residue Ser313, which is the site of Cdk-mediated USP1 phosphorylation, are also indicated.
Mentions: Transcription of the USP1 gene is regulated in a cell cycle-dependent manner. USP1 mRNA levels remain low during G1 phase, and reach a peak during S phase [55]. The cell cycle-dependent expression of USP1 is also regulated at the protein level by proteasomal degradation. In this regard, the USP1 region 295-342 (Figure 2) constitutes a destruction motif (degron) that is required for Anaphase Promoting Complex/CyclosomeCdh1 (APC/CCdh1)-dependent degradation of USP1 during G1 [71], which appears to be further modulated by calpains [72].

Bottom Line: Importantly, USP1 expression is deregulated in certain types of human cancer, suggesting that USP1 could represent a valid target in cancer therapy.We also summarize USP1 alterations found in cancer, combining data from the literature and public databases with our own data.Finally, we discuss the emerging potential of USP1 as a target, integrating published data with our novel findings on the effects of the USP1 inhibitor pimozide in combination with cisplatin in NSCLC cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Leioa, Spain.

ABSTRACT
Reversible protein ubiquitination is emerging as a key process for maintaining cell homeostasis, and the enzymes that participate in this process, in particular E3 ubiquitin ligases and deubiquitinases (DUBs), are increasingly being regarded as candidates for drug discovery. Human DUBs are a group of approximately 100 proteins, whose cellular functions and regulatory mechanisms remain, with some exceptions, poorly characterized. One of the best-characterized human DUBs is ubiquitin-specific protease 1 (USP1), which plays an important role in the cellular response to DNA damage. USP1 levels, localization and activity are modulated through several mechanisms, including protein-protein interactions, autocleavage/degradation and phosphorylation, ensuring that USP1 function is carried out in a properly regulated spatio-temporal manner. Importantly, USP1 expression is deregulated in certain types of human cancer, suggesting that USP1 could represent a valid target in cancer therapy. This view has gained recent support with the finding that USP1 inhibition may contribute to revert cisplatin resistance in an in vitro model of non-small cell lung cancer (NSCLC). Here, we describe the current knowledge on the cellular functions and regulatory mechanisms of USP1. We also summarize USP1 alterations found in cancer, combining data from the literature and public databases with our own data. Finally, we discuss the emerging potential of USP1 as a target, integrating published data with our novel findings on the effects of the USP1 inhibitor pimozide in combination with cisplatin in NSCLC cells.

Show MeSH
Related in: MedlinePlus