DLGH1 Is a Negative Regulator of T-Lymphocyte Proliferation

Stephenson, Linda M.; Sammut, Bénédicte; Graham, Daniel B.; Chan-Wang, Joaquim; Brim, Karry; Huett, Alan; Miletic, Ana V.; Kloeppel, Tracie; Landry, Aimee; Xavier, Ramnik J.; Swat, Wojciech

doi:10.1128/mcb.00439-07

Cited by 38 publications

(51 citation statements)

References 33 publications

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“…Loss of Dlg1 in T lymphocytes results in accelerated entry into S phase (Stephenson et al, 2007), and epithelial cells of the lens of Dlg1 gt/gt mutant mice show ectopic S-phase entry and increased proliferation (Nguyen et al, 2003b). Despite these defects, no widespread hyperproliferative syndromes in Dlg1-null mice have been reported (Mahoney et al, 2006;Stephenson et al, 2007). Indeed, in some Dlg1-null epithelial tissues decreased proliferation is actually observed (Iizuka-Kogo et al, 2007).…”

Section: Control Of Cell Proliferationmentioning

confidence: 99%

Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module

et al. 2008

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The neoplastic tumour suppressors, Scribble, Dlg and Lgl, originally discovered in the vinegar fly Drosophila melanogaster, are currently being actively studied for their potential role in mammalian tumourigenesis. In Drosophila, these tumour suppressors function in a common genetic pathway to regulate apicobasal cell polarity and also play important roles in the control of cell proliferation, survival, differentiation and in cell migration/invasion. The precise mechanism by which Scribble, Dlg and Lgl function is not clear; however, they have been implicated in the regulation of signalling pathways, vesicle trafficking and in the Myosin II-actin cytoskeleton. We review the evidence for the involvement of Scribble, Dlg, and Lgl in cancer, and how the various functions ascribed to these tumour suppressors in Drosophila and mammalian systems may impact on the process of tumourigenesis.

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Section: Control Of Cell Proliferationmentioning

confidence: 99%

Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module

et al. 2008

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“…In Dlgh1 fl/fl mice, exon 4 of the Dlgh1 gene is flanked upstream and downstream by loxP sites (33). Recombination that these sites produces a truncated transcript that is not translated into a functional protein (34).…”

Section: Methodsmentioning

confidence: 99%

“…Mice homozygous for this genotype were bred with nestin-Cre transgenic mice. Genotypes were confirmed by PCR as described previously (33), and depletion of SAP97 protein level was measured by Western blot analysis.…”

Section: Methodsmentioning

confidence: 99%

The role of SAP97 in synaptic glutamate receptor dynamics

Howard

Elias

et al. 2010

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

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106

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Proteins of the PSD-95-like membrane-associated guanylate kinase (PSD-MAGUK) family are vital for trafficking AMPA receptors (AMPARs) to synapses, a process necessary for both basal synaptic transmission and forms of synaptic plasticity. Synapse-associated protein 97 (SAP97) exhibits protein interactions, such as direct interaction with the GluA1 AMPAR subunit, and subcellular localization (synaptic, perisynaptic, and dendritic) unique within this protein family. Due in part to the lethality of the germline knockout of SAP97, this protein's role in synaptic transmission and plasticity is poorly understood. We found that overexpression of SAP97 during early development traffics AMPARs and NMDA receptors (NMDARs) to synapses, and that SAP97 rescues the deficits in AMPAR currents normally seen in PSD-93/-95 double-knockout neurons. Mature neurons that have experienced the overexpression of SAP97 throughout development exhibit enhanced AMPAR and NMDAR currents, as well as faster NMDAR current decay kinetics. In loss-of-function experiments using conditional SAP97 gene deletion, we recorded no deficits in glutamatergic transmission or long-term potentiation. These results support the hypothesis that SAP97 is part of the machinery that traffics glutamate receptors and compensates for other PSD-MAGUKs in knockout mouse models. However, due to functional redundancy, other PSD-MAGUKs can presumably compensate when SAP97 is conditionally deleted during development.AMPA | hippocampus | membrane-associated guanylate kinase | NMDA | postsynaptic density | synaptic transmission | synaptic development T he excitatory postsynaptic density (PSD) stabilizes AMPA receptors (AMPARs) and NMDA receptors (NMDARs) opposed to presynaptic terminals, providing a foundation for synaptic transmission and bidirectional receptor trafficking during plasticity. A major PSD component is the PSD-95-like membrane-associated guanylate kinase (PSD-MAGUK) protein family, which includes PSD-95/SAP90, PSD-93/Chapsyn-110, synapse-associated protein (SAP) 102, and SAP97, the mammalian homolog of Drosophila tumor-suppressor discs large (Dlg1) (1, 2), All PSD-MAGUKs contain protein-protein interaction motifs, most notably three PSD95/Dlg/ZO-1 (PDZ) domains (3-5), which provide a scaffold for synaptic protein complexes. PSD-95 and PSD-93 play critical roles in AMPAR trafficking at mature synapses, whereas SAP102 is most important during synaptogenesis (6-13). PSD-MAGUKs also are important for localizing NMDA receptors, especially during synapse development (14-17).Unlike other PSD-MAGUKs, SAP97β, the major isoform of the protein (also known as DLGH1; encoded by Dlgh1), is expressed at presynaptic and postsynaptic sites (2, 18) and perisynaptically in dendritic spines (19). SAP97β directly binds to AMPAR GluA1 subunits (20-23). Because SAP97 has been resistant to RNAi in our hands (but see 10) and germline KO causes lethal feeding deficits in neonatal mice (24), SAP97's synaptic function is uncertain and is based primarily on dissociated neuronal culture stu...

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“…We suspect that p38-dependent IL-10 production is mediated by TAB1. Non-classical p38 autophosphorylation via a p38 scaffold protein such as TAB1 [14], Dlgh1 [27,28], and so on that is a novel functional modulator of the p38 pathway negatively regulates the proliferative response of CD4 1 T cells. We showed an increase in the TAB1 gene and p38 autophosphorylation in anergic CD4 1 T cells, but there was no difference between the levels of ubiquitous TAB1 protein (72 kD) in naïve and anergic CD4 1 T cells.…”

Section: Il-10-producing Cd25mentioning

confidence: 99%

Targeted inhibition of IL‐10‐secreting CD25⁻ Treg via p38 MAPK suppression in cancer immunotherapy

et al. 2010

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Cancer-induced immunotolerance mediated by inducible Treg (iTreg) is a major obstacle to cancer immunotherapy. In a basic study of immunotolerance, injection of an endogenous superantigen, i.e. the minor lymphocyte stimulatory (Mls)-1 a , into specific TCR Vb8.1-Tg mice enabled generation of anergic CD25À iTreg, the immunosuppressive function of which was maintained by IL-10 production via p38-MAPK activation. Interestingly, although p38-chemical inhibitor (p38-inhibitor) is capable of breaking CD25 À iTreg-induced immunotolerance, the p38-inhibitor had hardly any immunotolerance breaking effect when CD25 1 Treg were present, suggesting that depletion of CD25 1 Treg is necessary for p38-inhibitor to be effective. Peptide OVA 323-339 iv.-injection into its specific TCR-Tg (OT-II) mice also induced adaptive tolerance by iTreg. Peptide immunotherapy with p38-inhibitor after CD25 1 Tregdepletion was performed in an OVA-expressing lymphoma E.G7-bearing tolerant model established by adoptive transfer of OT-II CD25 À iTreg, which resulted in suppression of tumor growth. Similarly, the antitumor immunity induced by peptide immunotherapy in colon carcinoma CT26-bearing mice, in which the number of IL-10-secreting iTreg is increased, was augmented by treatment with p38-inhibitor after CD25 1 Treg-depletion and resulted in inhibition of tumor progression. These results suggest that simultaneous inhibition of two distinct Treg-functions may be important to the success of cancer immunotherapy.

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DLGH1 Is a Negative Regulator of T-Lymphocyte Proliferation

Cited by 38 publications

References 33 publications

Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module

Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module

The role of SAP97 in synaptic glutamate receptor dynamics

Targeted inhibition of IL‐10‐secreting CD25⁻ Treg via p38 MAPK suppression in cancer immunotherapy

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DLGH1 Is a Negative Regulator of T-Lymphocyte Proliferation

Cited by 38 publications

References 33 publications

Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module

Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module

The role of SAP97 in synaptic glutamate receptor dynamics

Targeted inhibition of IL‐10‐secreting CD25− Treg via p38 MAPK suppression in cancer immunotherapy

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Targeted inhibition of IL‐10‐secreting CD25⁻ Treg via p38 MAPK suppression in cancer immunotherapy