Tight junction protein MAGI-1 is up-regulated by transfection with connexin 32 in an immortalized mouse hepatic cell line: cDNA microarray analysis

Murata, Masaki; Kojima, Takashi; Yamamoto, Takumi; Go, Mitsuru; Takano, Kenichi; Chiba, Hideki; Tokino, Takashi; Sawada, Norimasa

doi:10.1007/s00441-004-1017-0

Cited by 27 publications

(18 citation statements)

References 35 publications

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“…In contrast, the membrane-bound form of MAGI-1 has been implicated in the control of TJs (34), which are lost in HPVpositive cells (25,35,43). The results reported here show that this loss is indeed a result of E6 directing the degradation of MAGI-1.…”

Section: Discussionmentioning

confidence: 48%

“…Although there is no information on the potential role of MAGI-1 in the nucleus, previous studies have implicated the membrane-bound form of MAGI-1 in the establishment of cellular TJs (34). It has also been shown that TJs are disrupted in HPV-positive cells, and a possible role for hScrib in this phenotype has been suggested (35).…”

Section: Resultsmentioning

confidence: 99%

“…This PDZ binding potential renders these E6 proteins capable of interacting with, and potentially more importantly, targeting for proteasome-mediated degradation, a subset of PDZ domain-containing cellular substrates, including the cell polarity regulators human Dlg (hDlg) (11) and human Scribble (hScrib) (35), both of which are classified as potential tumor suppressor proteins (3,6,12,37,51,52). Other E6 PDZ domain-containing targets include the MAGI family of proteins (13,46), which are scaffolding molecules involved in the regulation of tight-junction (TJ) assembly (34). So far, at least 10 different PDZ domain-containing substrates of E6 have been described, including PSD95 (16), PATJ (25,43), MUPP1 (26), TIP1 (15), TIP2 (10), PTPN3 (20,49), PTPN13 (41), and CAL (19).…”

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confidence: 99%

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A Systematic Analysis of Human Papillomavirus (HPV) E6 PDZ Substrates Identifies MAGI-1 as a Major Target of HPV Type 16 (HPV-16) and HPV-18 Whose Loss Accompanies Disruption of Tight Junctions

Kranjec

Banks

2011

J Virol

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The E6 proteins from high-risk, cancer-causing types of human papillomavirus (HPV) are characterized by the presence of a PDZ (PSD95/Dlg/ZO-1) binding motif in their extreme carboxy termini, through which they interact with a number of cellular PDZ domain-containing substrates. In order to ascertain how many of these are degraded by E6 in vivo, we performed an extensive analysis of the effects of E6 ablation on the expression levels of a number of previously reported E6 PDZ substrates. Using HPV type 16 (HPV-16)-positive CaSKi cells and HPV-18-positive HeLa cells, we have found that MAGI-1 is a major degradation target of both HPV-16 and HPV-18 E6. In contrast, hDlg, hScrib, PTPN3, TIP2, FAP1, and PSD95 all exhibit various degrees of susceptibility to E6-induced degradation, and a high degree of HPV type specificity is observed for certain substrates. We also show that E6 preferentially targets MAGI-1 within the nucleus and at membrane sites. One of the direct consequences of MAGI-1 degradation is a loss of tight-junction integrity, as determined by mislocalization of the tight-junction protein ZO-1. Ablation of E6 expression restores tight junctions, and this restoration is dependent on the presence of MAGI-1. These results demonstrate that oncogenic HPV E6 proteins disrupt cellular tight junctions through the degradation of MAGI-1, and they provide further evidence of how the PDZ binding potential of E6 can contribute to HPV-induced malignancy.Human papillomaviruses (HPVs) are the causative agent of cervical cancer, which is brought about primarily by the combined action of two viral oncoproteins, E6 and E7 (reviewed in reference 55). These proteins target, respectively, the p53 (40, 50) and pRb (5, 9) tumor suppressors; they cooperate in the induction of keratinocyte immortalization (17, 33) and tumor formation in transgenic mice (14, 24); and they are required for the continued proliferation and survival of cervical-tumor-derived cell lines (21, 53). It is clear, however, that other cellular targets of both viral proteins are necessary for their full transforming activity. In the case of the high-risk HPV E6 oncoproteins, an interesting feature is the presence of a class 1 PDZ (PSD95/Dlg/ZO-1)-binding motif (PBM) at their carboxy termini (27), which is absent from E6 proteins derived from the low-risk HPV types. This PDZ binding potential renders these E6 proteins capable of interacting with, and potentially more importantly, targeting for proteasome-mediated degradation, a subset of PDZ domain-containing cellular substrates, including the cell polarity regulators human Dlg (hDlg) (11) and human Scribble (hScrib) (35), both of which are classified as potential tumor suppressor proteins (3, 6, 12, 37, 51, 52). Other E6 PDZ domain-containing targets include the MAGI family of proteins (13, 46), which are scaffolding molecules involved in the regulation of tight-junction (TJ) assembly (34). So far, at least 10 different PDZ domain-containing substrates of E6 have been described, including PSD95 (16), PATJ (25, ...

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Section: Discussionmentioning

confidence: 48%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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A Systematic Analysis of Human Papillomavirus (HPV) E6 PDZ Substrates Identifies MAGI-1 as a Major Target of HPV Type 16 (HPV-16) and HPV-18 Whose Loss Accompanies Disruption of Tight Junctions

Kranjec

Banks

2011

J Virol

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“…PAR3 is part of the PAR complex which localizes and controls the maturation of TJs, and PAR3 is one of the prime regulators of TJ formation. Thus, the fact that MAGI-1 enhances PAR3 junctional localization strongly suggests the involvement of MAGI-1 in the establishment of cell polarity by inducing the formation of apical junctional structures (56). These results demonstrate that the loss of TJs in HPV-18-positive HeLa cells is a direct consequence of the ability of E6 to direct the degradation of MAGI-1 and might provide an explanation as to why this protein is targeted by the virus during the life cycle and malignant progression.…”

Section: Discussionmentioning

confidence: 95%

Restoration of MAGI-1 Expression in Human Papillomavirus-Positive Tumor Cells Induces Cell Growth Arrest and Apoptosis

Kranjec

Massimi

Banks

2014

J Virol

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The cancer-causing high-risk human papillomavirus (HPV) E6 oncoproteins target a number of cellular proteins that contain PDZ domains. However, the role of many of these interactions in either the HPV life cycle or in HPV-induced malignancy remains to be defined. Previous studies had shown that MAGI-1 was one of the most strongly bound PDZ domaincontaining substrates of E6, and one consequence of this interaction appeared to facilitate the perturbation of tight junctions (TJs) by E6. In this study, we describe the generation of a mutation, K499E, within the MAGI-1 PDZ1 domain, which is resistant to E6 targeting. This mutant allows restoration of MAGI-1 expression in HPV-positive cells and defines additional activities of MAGI-1 that are overcome as a consequence of the association with E6. The reexpression of MAGI-1 in HPV-positive cells results in an increased recruitment of ZO-1 and PAR3 to sites of cell-cell contact, repression of cell proliferation, and induction of apoptosis. While the K499E mutation does not significantly affect these intrinsic activities of MAGI-1 in HPV-negative cells, its resistance to E6 targeting in an HPV-positive setting results in more cells expressing the mutant MAGI-1 than the wild-type MAGI-1, with a corresponding increase in TJ assembly, induction of apoptosis, and reduction in cell proliferation. These studies provide compelling evidence of a direct role for the perturbation of MAGI-1 function by E6 in the HPV life cycle and in HPV-induced malignancy. IMPORTANCEIt is clear that the targeting of PDZ-containing substrates by E6 is important for the normal viral life cycle and for the progression to malignancy. Nevertheless, which of these PDZ domain-containing proteins is relevant for HPV pathology is still elusive. In a previous study, we provided evidence that MAGI-1 is a sensitive proteolytic substrate for both the HPV-16 and HPV-18 E6 oncoproteins; however, the biological consequences associated with loss of MAGI-1 expression in HPVpositive cervical cancer cells are still poorly understood. Using a mutant MAGI-1, resistant to E6-mediated degradation, we show that its expression in cervical cancer cells promotes membrane recruitment of the tight junction-associated proteins ZO-1 and PAR3, represses cell proliferation, and promotes apoptosis. These findings suggest that E6-mediated inhibition of MAGI-1 function contributes to HPV pathology by perturbing tight junction assembly with concomitant stimulation of proliferation and inhibition of apoptosis. P apillomaviruses are a large and heterogeneous group of small nonenveloped DNA viruses able to infect vertebrates, including birds and reptiles (1, 2). The vast majority of human papillomaviruses (HPV) are causative agents of warts and self-remissive papillomas. However, a smaller group of HPV types, known as high-risk types, is associated with cancer onset in humans, where the most commonly caused malignancy is cervical cancer (3). The pathogenesis of cervical cancer is tightly linked to the combined action of E6 and E7,...

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“…Several MAGI-1 binding partners have been found. For example, β-catenin and actin-binding proteins act as binding partners of MAGI-1 [15,16]. In epithelia, MAGI-1 is localized at tight junctions [16].…”

Section: Magis Involved In Cancer Developmentmentioning

confidence: 99%

MAGI Scaffolding Molecules Involved in Cancer Cell Signaling

Matsuda

2013

J Carcinog Mutagen

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PTEN is a tumor suppressor gene inactivated in various human cancers, which antagonizes PI3K activity. The PI3K/AKT pathway is frequently activated in cancer, then, the PTEN tumor suppressor may be the major brake of the pathway. Cells that lack functional PTEN gene have constitutively higher levels of PIP3 and activated downstream targets. The PTEN protein binds to the MAGI proteins (MAGIs), which are scaffolding molecules with PDZ domain involved in the regulation of epithelial cell tight-junction assembly. Studies have revealed the potential relevance of the PDZ interactions to cancer cell behaviors. The molecular mechanisms contributing to cancer invasion are the subject of considerable investigation, as a better understanding of the pathogenesis will lead to the development of novel targeted therapies. We review recent studies on the features of PTEN and MAGIs in the signaling pathways involved in cancer progression.

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Tight junction protein MAGI-1 is up-regulated by transfection with connexin 32 in an immortalized mouse hepatic cell line: cDNA microarray analysis

Cited by 27 publications

References 35 publications

A Systematic Analysis of Human Papillomavirus (HPV) E6 PDZ Substrates Identifies MAGI-1 as a Major Target of HPV Type 16 (HPV-16) and HPV-18 Whose Loss Accompanies Disruption of Tight Junctions

A Systematic Analysis of Human Papillomavirus (HPV) E6 PDZ Substrates Identifies MAGI-1 as a Major Target of HPV Type 16 (HPV-16) and HPV-18 Whose Loss Accompanies Disruption of Tight Junctions

Restoration of MAGI-1 Expression in Human Papillomavirus-Positive Tumor Cells Induces Cell Growth Arrest and Apoptosis

MAGI Scaffolding Molecules Involved in Cancer Cell Signaling

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