TheHAUSP gene plays an important role in non-small cell lung carcinogenesis through p53-dependent pathways

Masuya, Daiki; Huang, Cheng; Liu, D; Nakashima, Takashi; Yokomise, Hiroyasu; Ueno, Masaki; Nakashima, Nariyasu; Sumitomo, Shinichi

doi:10.1002/path.1931

Cited by 92 publications

(67 citation statements)

References 30 publications

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“…For example, USP7 deubiquitinates the tumor suppressor protein, p53, thereby rescuing it from degradation, and reduced expression of this protease is linked to increased cancer incidence (28). In line with this finding, USP28 is involved in stabilizing the myc protooncogene (29).…”

Section: Discussionsupporting

confidence: 65%

A herpesvirus ubiquitin-specific protease is critical for efficient T cell lymphoma formation

Jarosinski

Kattenhorn

Kaufer

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The herpesvirus ubiquitin-specific protease (USP) family, whose founding member was discovered as a protease domain embedded in the large tegument protein of herpes simplex virus 1 (HSV-1), is conserved across all members of the Herpesviridae. Whether this conservation is indicative of an essential function of the enzyme in vivo has not yet been established. As reported here, USP activity is conserved in Marek's disease virus (MDV), a tumorigenic alphaherpesvirus. A single amino acid substitution that abolishes the USP activity of the MDV large tegument protein diminishes MDV replication in vivo, and severely limits the oncogenic potential of the virus. Expression of the USP transcripts in MDV-transformed cell lines further substantiates this hypothesis. The herpesvirus USP thus appears to be required not only to maintain a foothold in the immunocompetent host, but also to contribute to malignant outgrowths.chicken ͉ deubiquitinating enzyme ͉ herpes ͉ Marek's disease virus T he ubiquitin-proteasome system controls cytosolic proteolysis, certain aspects of transcription, antigen presentation via major histocompatibility complex (MHC) class I products, and the trafficking of surface-exposed receptors (1-5). As for many other posttranslational modifications, both ubiquitin conjugation and its reversal by ubiquitin-specific proteases (USPs) determine the biological outcome of the reaction. The enzyme families that catalyze ubiquitin conjugation and removal are quite diverse (6-9). Consequently, bioinformatic analysis is not always adequate to identify novel USPs. To target such enzymes biochemically, we developed activity-based probes for USPs and enzymes that act on ubiquitin-like modifiers (10). These probes are equipped with an affinity handle to allow retrieval and identification of the enzymes targeted by the electrophilic warhead installed at the probe's carboxyl terminus.Through the use of one of these probes, HA-ubiquitin vinylmethylester (HA-UbVME), we identified the large tegument protein of herpes simplex virus 1 (HSV-1), viral protein (VP) 1/2, encoded by the unique-long (U L ) 36 gene, as the source of an active USP. Its sequence showed no obvious similarity to known eukaryotic USPs and failed to yield an obvious signature of residues diagnostic of known cysteine protease families. Nonetheless, sequence comparisons across the Herpesviridae show the presence of a few absolutely conserved residues (Cys, Asp, His, Glu), all of which are consistent with involvement in a potential thiol protease active site. We have, meanwhile, confirmed both the mechanism of action of such ubiquitin-based probes (11)(12)(13)(14)(15) and the identity of the viral cysteine protease domain as an authentic USP by crystallographic analysis of the homologous segment of the murine cytomegalovirus (MCMV) M48 protein (16). Notwithstanding the conservation of the identified USP activity in all herpesviruses, we do not know whether this activity makes a contribution to the replicative success and pathogenicity of herpesviruses in vivo...

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Section: Discussionsupporting

confidence: 65%

A herpesvirus ubiquitin-specific protease is critical for efficient T cell lymphoma formation

Jarosinski

Kattenhorn

Kaufer

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…There is growing evidence that HAUSP downregulation might play a role in tumorigenesis, as shown in a study on non-small cell lung cancer patients. 37 Our study provides further evidence that NBs suffer from a derailed Hdm2/ HAUSP regulation of p53, either via HAUSP dysfunction (this study) or hyperactive Hdm2 3,14,30 both resulting in cytoplasmic sequestration due to enhanced nuclear export and possibly impaired re-import. Perhaps most importantly, this study also shows that nongenotoxic targeted drugs of the Nutlin type that are currently under development are able to reverse this dysregulated p53-Hdm2-HAUSP axis in NB.…”

Section: Discussionsupporting

confidence: 67%

Hyperubiquitylation of wild-type p53 contributes to cytoplasmic sequestration in neuroblastoma

et al. 2007

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Neuroblastoma (NB) is the most common solid malignancy in childhood and its prognosis is still generally poor. In contrast to many other cancers, mutations of the p53 tumor suppressor are rare. Instead, significant cytosolic sequestration of wtp53 is one of several mechanisms that attenuate p53 function in this cancer. Here, we report that aberrant p53 hyperubiquitylation contributes to p53 cytoplasmic sequestration in NB. NB lines constitutively harbor an elevated portion of wtp53 as stable ubiquitylated species confined to the cytoplasm. p53 hyperubiquitylation is not due to dysregulation by Hdm2 or proteasomal dysfunction. Instead, the defect lies in p53 regulation by HAUSP, a major p53-deubiquitylating enzyme. In contrast to non-NB cancer cells with nuclear p53 and normal ubiquitylation, p53 from NB cells shows impaired HAUSP interaction. Conversely, interference with p53 hyperubiquitylation in NB cells by Nutlin 3a or by a C-terminal p53 peptide (aa 305-393) results in p53 relocalization from the cytoplasm to the nucleus, and in case of Nutlin, in reactivation of p53's transcriptional and apoptotic functions. Moreover, nutlin and camptothecin act synergistically in inducing NB cell apoptosis. Hence, this study strengthens the rationale for targeting p53 deubiquitylation by drugs like Nutlin as a promising new strategy in NB therapy. Neuroblastoma (NB) is the most common solid malignancy in childhood and still accounts for more pediatric cancer deaths than any other cancer type. 1 The p53 tumor suppressor induces cell growth arrest, apoptosis and senescence in response to various types of stress and is mutated in over 50% of cancers. 2 However, in NB p53 mutations are exceedingly rare and occur in o2%, typically in relapsed tumors after therapy. 3,4 Instead, subcellular mislocalization of wtp53 with constitutive cytoplasmic sequestration represents one of several alternative mechanisms to inactivate p53 function in this cancer. Moll et al. 5 originally found cytoplasmic accumulation of p53 in 96% of primary undifferentiated NB tumors, whereas differentiated tumors (ganglioneuromas) lacked detectable levels of p53. Although some NB lines show predominantly nuclear p53 staining, 6 many NB cell lines also exhibit abnormal cytoplasmic p53 localization. [7][8][9][10][11][12][13] Cytoplasmic sequestration of wtp53 correlates with attenuation of DNA damage-induced G1 arrest 6,7 and apoptosis 13,14 in NB cell lines, since this interferes with p53's function as a transcription factor in the nucleus. Furthermore, Wolff et al. 15 reported that wtp53 in NB is in a conformation that is refractory to integration into transcriptional complexes, adding to transcriptional inactivity.In growing, unstressed cells p53 levels are very low owing to rapid degradation via the ubiquitin-proteasome pathway. Hdm2, the major E3 ligase which itself is a target gene of p53, ubiquitylates p53, thus constituting a negative-feedback loop. 16,17 Importantly, this ubiquitylation of p53 is required for its nuclear export via the export recepto...

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“…Mutations in CYLD have been associated with cylindromatosis, Brooke-Spiegler syndrome, and familial trichoepithelioma, all of which are predisposed to multiple skin tumors of the head and neck (13). Additionally, downregulation of USP7 has been linked with non-small cell lung carcinoma, and in conjunction with p53 status, USP7 was shown to be a prognostic marker for adenocarcinoma patients (14).…”

Section: Introductionmentioning

confidence: 99%

The Deubiquitinating Enzyme USP17 Is Highly Expressed in Tumor Biopsies, Is Cell Cycle Regulated, and Is Required for G1-S Progression

et al. 2010

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Ubiquitination is a reversible posttranslational modification that is essential for cell cycle control, and it is becoming increasingly clear that the removal of ubiquitin from proteins by deubiquitinating enzymes (DUB) is equally important. In this study, we have identified high levels of the DUB USP17 in several tumor-derived cell lines and primary lung, colon, esophagus, and cervix tumor biopsies. We also report that USP17 is tightly regulated during the cell cycle in all the cells examined, being abundantly evident in G 1 and absent in S phase. Moreover, regulated USP17 expression was necessary for cell cycle progression because its depletion significantly impaired G 1 -S transition and blocked cell proliferation. Previously, we have shown that USP17 regulates the intracellular translocation and activation of the GTPase Ras by controlling Ras-converting enzyme 1 (RCE1) activation. RCE1 also regulates the processing of other proteins with a CAAX motif, including Rho family GTPases. We now show that USP17 depletion blocks Ras and RhoA localization and activation. Moreover, our results confirm that USP17-depleted cells have constitutively elevated levels of the cyclin-dependent kinase inhibitors p21 cip1 and p27 kip1 , known downstream targets of Ras and RhoA signaling. These observations clearly show that USP17 is tightly regulated during cell division and that its expression is necessary to coordinate cell cycle progression, and thus, it may be considered a promising novel cancer therapeutic target.

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TheHAUSP gene plays an important role in non-small cell lung carcinogenesis through p53-dependent pathways

Cited by 92 publications

References 30 publications

A herpesvirus ubiquitin-specific protease is critical for efficient T cell lymphoma formation

A herpesvirus ubiquitin-specific protease is critical for efficient T cell lymphoma formation

Hyperubiquitylation of wild-type p53 contributes to cytoplasmic sequestration in neuroblastoma

The Deubiquitinating Enzyme USP17 Is Highly Expressed in Tumor Biopsies, Is Cell Cycle Regulated, and Is Required for G1-S Progression

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