PDZ-containing proteins: alternative splicing as a source of functional diversity

Sierralta, Jimena; Mendoza, C.

doi:10.1016/j.brainresrev.2004.06.002

Cited by 40 publications

(32 citation statements)

References 107 publications

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“…ZO1 mediates a broad range of interactions between tight junctions and the cytoskeleton [9]. Despite having numerous binding domains, it is still not clear whether ZO1 has functions that are more specific than participation in tight junction-cytoskeletal interactions.…”

Section: Discussionmentioning

confidence: 99%

“…A second type of regulatory region on Cx43 is the PDZ-binding domain located on the very C-terminus [8]. PDZ-based interactions of Cx43 with the tight junction protein, ZO1, control further interactions with numerous cytoskeletal, tight, and adherent junction proteins through ZO1 [1,9]. Data reviewed by Giepmans demonstrates a close relationship between gap junction communication and tight junctions: many cell lines demonstrate inhibited gap junction communication after disruption of tight junctions [10].…”

Section: Introductionmentioning

confidence: 99%

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ZO-1 is required for protein kinase C gamma-driven disassembly of connexin 43

Akoyev

Takemoto

2007

Cellular Signalling

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We have previously reported that protein kinase C gamma (PKCγ) is activated by phorbol-12-myristate-13-acetate (TPA) and that this causes PKCγ translocation to membranes and phosphorylation of the gap junction protein, connexin 43 (Cx43). This phosphorylation, on S368 of Cx43, causes disassembly of Cx43 out of cell junctional plaques resulting in the inhibition of dye transfer. The purpose of this study is to identify the specific role of zonula occludens protein-1 (ZO-1), a tight junction protein with recently established effects on gap junctions, in this PKCγ-driven Cx43 disassembly. For this purpose, ZO-1 levels in lens epithelial cells in culture were decreased by up to 70% using specific siRNA. The down-regulation of ZO-1 caused a stable interaction of PKCγ with Cx43 even without normal enzyme activation by TPA. However, after TPA activation of the PKCγ, the Cx43 did not disassemble out of plaques even though the PKCγ enzyme was activated and the Cx43 was phosphorylated on S368. Confocal microscopy demonstrated that the siRNA treatment caused a loss of ZO-1 from borders of large junctional Cx43 cell-to-cell plaques and resulted in the accumulation of Cx43 aggregates inside of cells. Loss of the specific "plaquetosome" arrangement of large Cx43 plaques surrounded by ZO-1 was accompanied by a complete loss of functional dye transfer. These results suggest that ZO-1 is required for Cx43 control, both for dye transfer, and, for the PKCγ-driven disassembly response.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ZO-1 is required for protein kinase C gamma-driven disassembly of connexin 43

Akoyev

Takemoto

2007

Cellular Signalling

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“…Five of them were valuated at high confidence level. Alternative splicing is an important mechanism to generate protein diversity and to determine the binding properties, intracellular localization, enzymatic activity, protein stability and posttranslational modifications of proteins in a tissue-specific or development-specific way (Sierralta and Mendoza, 2004;Cooper, 2005;Lee and Wang, 2005;Stamm et al, 2005). Splice site mutations of tumor suppressor genes often create truncated proteins as classical nonsense mutations.…”

Section: Discussionmentioning

confidence: 99%

Expression of GCIP in transgenic mice decreases susceptibility to chemical hepatocarcinogenesis

Xia

Stafford

et al. 2006

Oncogene

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Transcription factors with helix-loop-helix (HLH) motif play critical roles in controlling the expression of genes involved in lineage commitment, cell fate determination, proliferation, and tumorigenesis. To examine whether the newly identified HLH protein GCIP/CCNDBP1 modulates cell fate determination and plays a role in hepatocyte growth, proliferation, and hepatocarcinogenesis, we generated transgenic mice with human GCIP gene driven by a liver-specific albumin promoter. We demonstrated that in GCIP transgenic mice, the overall liver growth and regeneration occurred normally after liver injury induced by carbon tetrachloride (CCl 4 ). In the diethylnitrosamine (DEN)-induced mouse hepatocarcinogenesis, we demonstrated that overexpression of GCIP in mouse liver suppressed DEN-induced hepatocarcinogenesis at an early stage of tumor development. The number of hepatic adenomas at 24 weeks was significantly lower or not detected in GCIP transgenic male mice compared to the control mice under the same treatment. Although GCIP has little inhibition on the number of hepatic tumors at later stages (40 weeks), hepatocellular tumors in GCIP transgenic mice are smaller and well-differentiated compared to the poorly differentiated tumors in wildtype mice. Furthermore, we demonstrate that GCIP functions as a transcriptional suppressor, regulates the expression of cyclin D1, and inhibits anchorage-independent cell growth and colony formation in HepG2 cells, suggesting a significant role of GCIP in tumor initiation and development.

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“…The expression of PDZ-domain-encoding genes is often regulated at the level of mRNA splicing, which gives rise to cell-type-and/or stage-specific isoforms that can differ in their capacity to interact with other proteins (Sierralta and Mendoza, 2004). For example, in Drosophila, alternative splicing of dlg transcripts gives rise to an epithelia-specific isoform, DlgA, which lacks the L27 domain and is therefore unable to bind to Lin-7, and another isoform, DlgS97, which contains the L27 domain and can associate with Lin-7 in the neuromuscular junction (Bachmann et al, 2004;Mendoza et al, 2003).…”

Section: Different Isoforms Obtained By Alternative Splicingmentioning

confidence: 99%

The Crumbs complex: from epithelial-cell polarity to retinal degeneration

Bulgakova

Knust

2009

Journal of Cell Science

215

217

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The evolutionarily conserved Crumbs protein complex is a key regulator of cell polarity and cell shape in both invertebrates and vertebrates. The important role of this complex in normal cell function is illustrated by the finding that mutations in one of its components, Crumbs, are associated with retinal degeneration in humans, mice and flies. Recent results suggest that the Crumbs complex plays a role in the development of other disease processes that are based on epithelial dysfunction, such as tumorigenesis or the formation of cystic kidneys. Localisation of the complex is restricted to a distinct region of the apical plasma membrane that abuts the zonula adherens in epithelia and photoreceptor cells of invertebrates and vertebrates, including humans. In addition to the core components, a variety of other proteins can be recruited to the complex, depending on the cell type and/or developmental stage. Together with diverse post-transcriptional and posttranslational mechanisms that regulate the individual components, this provides an enormous functional diversity and flexibility of the complex. In this Commentary, we summarise findings concerning the organisation and modification of the Crumbs complex, and the conservation of its constituents from flies to mammals. In addition, we discuss recent results that suggest its participation in various human diseases, including blindness and tumour formation.

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PDZ-containing proteins: alternative splicing as a source of functional diversity

Cited by 40 publications

References 107 publications

ZO-1 is required for protein kinase C gamma-driven disassembly of connexin 43

ZO-1 is required for protein kinase C gamma-driven disassembly of connexin 43

Expression of GCIP in transgenic mice decreases susceptibility to chemical hepatocarcinogenesis

The Crumbs complex: from epithelial-cell polarity to retinal degeneration

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