Human scribble, a novel tumor suppressor identified as a target of high‐risk HPV E6 for ubiquitin‐mediated degradation, interacts with adenomatous polyposis coli

Takizawa, Shin‐ya; Nagasaka, Kazunori; Nakagawa, Shunsuke; Yano, Tetsu; Nakagawa, Keiichi; Yasugi, Toshiharu; Takeuchi, Takamasa; Kanda, Tadahito; Huibregtse, Jon M.; Akiyama, Tetsu; Taketani, Yuji

doi:10.1111/j.1365-2443.2006.00954.x

Cited by 67 publications

(72 citation statements)

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“…Highrisk E6 binds to the adherens junction (AJ)-localized PDZ proteins Dlg (24) and Scribble (36). They have been proposed to act as negative regulators of the cell cycle (20,62) and may thereby alter cell growth control. MUPP1 is a paralog of PATJ, based on its sequence homology and its ability to bind PALS1 (49).…”

Section: Discussionmentioning

confidence: 99%

PATJ, a Tight Junction-Associated PDZ Protein, Is a Novel Degradation Target of High-Risk Human Papillomavirus E6 and the Alternatively Spliced Isoform 18 E6*

Storrs

Silverstein

2007

J Virol

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The E6 protein from high-risk human papillomavirus types interacts with and degrades several PDZ domain-containing proteins that localize to adherens junctions or tight junctions in polarized epithelial cells. We have identified the tight junction-associated multi-PDZ protein PATJ (PALS1-associated TJ protein) as a novel binding partner and degradation target of high-risk types 16 and 18 E6. PATJ functions in the assembly of the evolutionarily conserved CRB-PALS1-PATJ and Par6-aPKC-Par3 complexes and is critical for the formation of tight junctions in polarized cells. The ability of type 18 E6 full-length to bind to, and the subsequent degradation of, PATJ is dependent on its C-terminal PDZ binding motif. We demonstrate that the spliced 18 E6* protein, which lacks a C-terminal PDZ binding motif, associates with and degrades PATJ independently of full-length 18 E6. Thus, PATJ is the first binding partner that is degraded in response to both isoforms of 18 E6. The ability of E6 to utilize a non-E6AP ubiquitin ligase for the degradation of several PDZ binding partners has been suggested. We also demonstrate that 18 E6-mediated degradation of PATJ is not inhibited in cells where E6AP is silenced by shRNA. This suggests that the E6-E6AP complex is not required for the degradation of this protein target.Human papillomaviruses (HPVs) are DNA tumor viruses that infect basal cells of the mucosal or cutaneous epithelium, where they cause proliferative lesions on genital tissues, the upper respiratory tract, and skin. Papillomas induced by highrisk mucosal HPV types, of which 16, 18, 31, and 45 are predominant, are inherently oncogenic and associated with the vast majority of cervical cancers (64) and many oral cancers (9). In contrast, low-risk types, such as 6 and 11, are rarely associated with carcinogenesis (10). HPV-associated carcinogenesis is attributed to the high-risk specific activities of the viral gene products E6 and E7, and introduction of these genes from HPV types 16 or 18 can induce immortalization of primary human keratinocytes (16,35). Studies using transgenic mice that express 16 E6 and/or 16 E7 have revealed that E7 initiates tumor formation, while E6 induces tumor promotion and progression, in the skin and cervix of transgenic animals (13, 47, 58).High-risk E6 proteins are multifunctional and associate with functionally diverse cellular proteins. Degradation of p53 by the E6-E6AP complex (17) is a property of high-risk E6 types, although this activity alone is not sufficient for E6-dependent immortalization activity in tissue culture or tumorigenesis in transgenic animals. For example, certain E6 mutant proteins that fail to degrade p53 retain their ability to immortalize primary cells (30,45). Moreover, the phenotypes of E6 transgenic mice are not observed in p53-null mice (59).A 4-amino-acid PDZ binding motif (X-S/T-X-V/L, where X is any amino acid) is present at the carboxy termini of all known high-risk mucosal HPV E6 proteins. The conservation of this motif among high-risk, but not low-risk, muco...

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Section: Discussionmentioning

confidence: 99%

PATJ, a Tight Junction-Associated PDZ Protein, Is a Novel Degradation Target of High-Risk Human Papillomavirus E6 and the Alternatively Spliced Isoform 18 E6*

Storrs

Silverstein

2007

J Virol

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“…The human homologs of the Drosophila tumor suppressors Dlg and Scribble (hDlg and hScrib) are cell adhesion proteins that interact with adenomatous polyposis coli (APC) and are targeted for degradation by HPV E6. 25,26 Inhibiting the APC/hScrib interaction disrupts adherens junctions important in cell adhesion, 25 whereas loss of the hDlg/APC interaction reduces the negative regulation of entry into S-phase of the cell cycle. 26 In common with many other cell adhesion proteins, hDlg and hScrib contain PDZ domains.…”

Section: Cell Adhesionmentioning

confidence: 99%

Human papillomavirus and molecular considerations for cancer risk

Whiteside

Siegel

Unger

2008

Cancer

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Human papillomaviruses (HPVs) are a major cause of cancer globally, including cervical cancer. The HPV 'early' proteins, E6 and E7, are the chief oncoproteins involved in cancer progression. These oncoproteins are more highly expressed in high-grade dysplasias and invasive cancer coincident with reduced viral DNA replication and reduced production of infective progeny virions. The E6 and E7 oncoproteins interact with several cellular proteins-classically TP53 and RB1, respectively-leading to the degradation of several of these proteins, although all interactions do not necessarily result in the degradation of a cellular protein.HPV infection is also associated with viral and host DNA methylation changes, many of which also occur in cancer types not associated with HPV infection. The E6 and E7 interactions with cellular proteins and DNA methylation changes are associated with changes in the integrity of key cellular pathways that regulate genomic integrity, cell adhesion, the immune response, apoptosis, and cell cycle control. The alterations in key cellular pathways may provide useful biomarkers to improve the sensitivity of current cancer screening methods, such as the Papanicolaou test. This review provides a detailed summary of the interactions of E6 and E7 with cellular proteins and alterations in cellular DNA methylation associated with HPV infection. The importance of molecular biomarkers to the clinical setting, underserved populations, and general public health is discussed.

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“…SCRIB encodes a large, 220-kDa cytoplasmic scaffolding protein that comprises a large leucine-rich repeat (LRR) region and 4 PDZ domains that regulate protein-protein interactions (5,7), including SCRIB-LLGL2 (19). Other reported SCRIB binding partners include the tight junction protein ZO-2 (20), the planar cell polarity protein VANGL2 (19), the tumor suppressor adenomatous polyposis coli (APC) (21), and the MAPK signaling molecule ERK (22). In fact, previous in vitro work undertaken in our labora-tory and others has indicated that SCRIB may negatively regulate the RAS/MAPK cascade to maintain polarity and tissue homeostasis (22,23).…”

Section: Introductionmentioning

confidence: 99%

SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia

Pearson¹,

Pérez–Mancera²,

Dow³

et al. 2011

J. Clin. Invest.

162

195

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Loss of cellular polarity is a hallmark of epithelial cancers, raising the possibility that regulators of polarity have a role in suppressing tumorigenesis. The Scribble complex is one of at least three interacting protein complexes that have a critical role in establishing and maintaining epithelial polarity. In human colorectal, breast, and endometrial cancers, expression of the Scribble complex member SCRIB is often mislocalized and deregulated. Here, we report that Scrib is indispensable for prostate homeostasis in mice. Scrib heterozygosity initiated prostate hyperplasia, while targeted biallelic Scrib loss predisposed mice to prostate intraepithelial neoplasia. Mechanistically, Scrib was shown to negatively regulate the MAPK cascade to suppress tumorigenesis. Further analysis revealed that prostate-specific loss of Scrib in mice combined with expression of an oncogenic Kras mutation promoted the progression of prostate cancer that recapitulated the human disease. The clinical significance of the work in mice was highlighted by our observation that SCRIB deregulation strongly correlated with poor survival in human prostate cancer. These data suggest that the polarity network could provide a new avenue for therapeutic intervention.

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Human scribble, a novel tumor suppressor identified as a target of high‐risk HPV E6 for ubiquitin‐mediated degradation, interacts with adenomatous polyposis coli

Cited by 67 publications

References 50 publications

PATJ, a Tight Junction-Associated PDZ Protein, Is a Novel Degradation Target of High-Risk Human Papillomavirus E6 and the Alternatively Spliced Isoform 18 E6*

PATJ, a Tight Junction-Associated PDZ Protein, Is a Novel Degradation Target of High-Risk Human Papillomavirus E6 and the Alternatively Spliced Isoform 18 E6*

Human papillomavirus and molecular considerations for cancer risk

SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia

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