The human UNP locus at 3p21.31 encodes two tissue-selective, cytoplasmic isoforms with deubiquitinating activity that have reduced expression in small cell lung carcinoma cell lines

Frederick, A. Matsen; Rolfe, Mark; Mi, Chiu

doi:10.1038/sj.onc.1201537

Cited by 51 publications

(70 citation statements)

References 19 publications

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“…Both USP4 and USP15 contain putative nuclear localization signals (NLSs), with that of USP4 being very similar to that of p53 (11,13). Overexpression of transfected myc epitope-tagged USP4 in IMR90 cells revealed either whole-cell or cytoplasmic staining (17). However, the overexpression of USP4 in these experiments could affect its location.…”

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confidence: 69%

“…The ostensibly disparate results of Gupta et al (12) and Frederick et al (17) are completely consistent with our results. Endogenous Usp4 was detected mainly in the nucleus of mouse NIH3T3 cells (12), whereas the overexpressed human ortholog of Usp4 was located mainly in the cytoplasm in IMR90 human lung fibroblasts (17). Thus, factors such as cell type, stage of the cell cycle, or level of expression appear to influence the localization of a shuttling protein, changing the equilibrium to render it more nuclear or more cytoplasmic.…”

Section: Discussionmentioning

confidence: 99%

“…For example, Gupta et al (12,13) generated anti-peptide antibodies, which reacted with a 180-kDa protein in NIH3T3 cell lysates instead of the predicted 110 kDa for Usp4. Frederick et al (17) raised a peptide antibody against a region of USP4 almost identical to the subsequently identified USP15 (4) (USP4, CHFSKADTIA-TIEK; USP15, RRFSKADTIDTIEK; identical residues are underlined). Finally, we found that the commercial anti-USP4 (UNP) antibody (Zymed Laboratories Inc.), raised by DeSalle et al (19) against a C-terminal peptide of human USP4, crossreacted with recombinant Usp15 (Fig.…”

Section: Generation Of Usp4-and Usp15-specific Antibodies-severalmentioning

confidence: 99%

“…In a study of primary human lung tumor tissue, Gray et al (14) observed that the human homolog of Usp4, USP4 (UNP; also termed Unph), had consistently elevated gene expression levels in small cell tumors and adenocarcinomas of the lung, suggesting a possible causative role for this UBP in neoplasia. In a separate study using cell lines rather than primary tissue, USP4 protein levels were shown to be slightly but consistently reduced in cell lines derived from small cell tumors, leading to the suggestion that USP4 may be a candidate tumor suppressor gene (17). Recently, both mouse and human Usp4 have been shown to interact with the Rb family of tumor suppressor proteins, a possible mechanism for Usp4-mediated cell transformation (18,19).…”

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confidence: 99%

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Nuclear-Cytoplasmic Shuttling of the Oncogenic Mouse UNP/USP4 Deubiquitylating Enzyme

Soboleva

Jans

Johnson-Saliba

et al. 2005

Journal of Biological Chemistry

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The oncogenic deubiquitylating enzyme (DUB) Unp/ Usp4, which binds to the retinoblastoma family of tumor suppressor proteins, was originally described as a nuclear protein. However, more recent studies have shown it to be cytoplasmic. In addition, analysis of its subcellular localization has been complicated by the existence of the paralog Usp15. In this study, we resolved this controversy by investigating the localization of exogenously expressed Usp4 (using red fluorescent proteinUsp4) and of endogenous Usp4 (using highly specific antibodies that can distinguish Usp4 from Usp15). We found that by inhibiting nuclear export with leptomycin B, both exogenous and endogenous Usp4 accumulate in the nucleus. Further, using a Rev-green fluorescent protein-based export assay, we confirmed the existence of a nuclear export signal ( 133 VEVYLLELKL 142 ) in Usp4. In addition, a functional nuclear import signal ( 766 QPQKKKK 772 ) was also identified, which was specifically recognized by importin ␣/␤. Finally, we show that the equilibrium of Usp4 subcellular localization varies between different cell types. Usp4 is thus the first DUB reported to have nucleocytoplasmic shuttling properties. The implications of this shuttling for its function as a DUB are discussed.

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confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Generation Of Usp4-and Usp15-specific Antibodies-severalmentioning

confidence: 99%

mentioning

confidence: 99%

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Nuclear-Cytoplasmic Shuttling of the Oncogenic Mouse UNP/USP4 Deubiquitylating Enzyme

Soboleva

Jans

Johnson-Saliba

et al. 2005

Journal of Biological Chemistry

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“…Interestingly, USP4, originally characterized as an oncogene by its ability to transform NIH3T3 cells (Gupta et al, 1994), maps at 3p21.3, a locus frequently rearranged in human tumor cells. This gene is overexpressed in several types of human cancer (Gray et al, 1995;Zhang et al, 2011b), and downregulated in small cell lung cancer cell lines (Frederick et al, 1998). Moreover, high levels of USP17 have been identified in primary lung, colon, esophagus and cervix tumor biopsies (McFarlane et al, 2010).…”

Section: Genetic or Functional Alterations Of Dubs In Cancermentioning

confidence: 99%

Deubiquitinases in cancer: new functions and therapeutic options

et al. 2011

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Deubiquitinases (DUBs) have fundamental roles in the ubiquitin system through their ability to specifically deconjugate ubiquitin from targeted proteins. The human genome encodes at least 98 DUBs, which can be grouped into 6 families, reflecting the need for specificity in their function. The activity of these enzymes affects the turnover rate, activation, recycling and localization of multiple proteins, which in turn is essential for cell homeostasis, protein stability and a wide range of signaling pathways. Consistent with this, altered DUB function has been related to several diseases, including cancer. Thus, multiple DUBs have been classified as oncogenes or tumor suppressors because of their regulatory functions on the activity of other proteins involved in tumor development. Therefore, recent studies have focused on pharmacological intervention on DUB activity as a rationale to search for novel anticancer drugs. This strategy may benefit from our current knowledge of the physiological regulatory mechanisms of these enzymes and the fact that growth of several tumors depends on the normal activity of certain DUBs. Further understanding of these processes may provide answers to multiple remaining questions on DUB functions and lead to the development of DUB-targeting strategies to expand the repertoire of molecular therapies against cancer.

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Human genetic diseases of proteolysis

Kato

1999

Hum. Mutat.

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The human UNP locus at 3p21.31 encodes two tissue-selective, cytoplasmic isoforms with deubiquitinating activity that have reduced expression in small cell lung carcinoma cell lines

Cited by 51 publications

References 19 publications

Nuclear-Cytoplasmic Shuttling of the Oncogenic Mouse UNP/USP4 Deubiquitylating Enzyme

Nuclear-Cytoplasmic Shuttling of the Oncogenic Mouse UNP/USP4 Deubiquitylating Enzyme

Deubiquitinases in cancer: new functions and therapeutic options

Human genetic diseases of proteolysis

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