Keratin 8/18 regulation of insulin receptor signaling and trafficking in hepatocytes through a concerted phosphoinositide-dependent Akt and Rab5 modulation [Research]
Keratins (Ks) are epithelial cell intermediate filament (IF) proteins that are expressed as pairs in a differentiation-regulated manner. Hepatocyte IFs are made only of K8/K18 pairs, which means that a K8 loss in K8-null mice leads to degradation of K18. Functionally, there is accumulating evidence that IFs contribute to signaling platforms. Here, we investigate the role of K8/K18 IFs in the regulation of insulin receptor (IR) signaling and trafficking in hepatocytes. We find that the IR substrate 1 (IRS1)/PI3K/Akt signaling cascade—downstream of IR—displays prolonged activation in K8-null compared with wild-ty...
Source: FASEB Journal - August 1, 2017 Category: Biology Authors: Roux, A., Loranger, A., Lavoie, J. N., Marceau, N. Tags: Research Source Type: research
Bim gene dosage is critical in modulating nephron progenitor survival in the absence of microRNAs during kidney development [Research]
In this study, we generated a compound mouse model with conditional deletion of both Dicer and Bim, to determine the biologic significance of increased Bim expression in Dicer-deficient nephron progenitors. The loss of Bim partially restored the number of nephron progenitors and improved nephron formation. The number of progenitors undergoing apoptosis was significantly reduced in kidneys with loss of a single allele, or both alleles, of Bim compared to mutant kidneys. Furthermore, 2 miRNAs expressed in nephron progenitors (miR-17 and miR-106b) regulated Bim levels in vitro and in vivo. Together, these data suggest that mi...
Source: FASEB Journal - August 1, 2017 Category: Biology Authors: Cerqueira, D. M., Bodnar, A. J., Phua, Y. L., Freer, R., Hemker, S. L., Walensky, L. D., Hukriede, N. A., Ho, J. Tags: Research Source Type: research
PGLP-1, a novel long-acting dual-function GLP-1 analog, ameliorates streptozotocin-induced hyperglycemia and inhibits body weight loss [Research]
It is well known that glucagon-like peptide 1 (GLP-1) has antidiabetic action. It has 2 distinct functions, an insulinotropic effect dependent on GLP-1 receptor (GLP-1R) and an insulinomimetic effect independent of GLP-1R. However, use of GLP-1 in vivo is limited by its short half-life. Therefore, our lab designed PGLP-1, a novel 2-function candidate peptide as a potential substitute. Using a streptozotocin-induced hyperglycemic mouse model, we demonstrated in vitro and in vivo that PGLP-1 had insulinotropic actions dependent on GLP-1R and insulinomimetic functions independent of GLP-1R. PGLP-1 treatment increased islet &b...
Source: FASEB Journal - August 1, 2017 Category: Biology Authors: Gao, H., Zhao, Q., Song, Z., Yang, Z., Wu, Y., Tang, S., Alahdal, M., Zhang, Y., Jin, L. Tags: Research Source Type: research
Epithelial Src homology region 2 domain-containing phosphatase-1 restrains intestinal growth, secretory cell differentiation, and tumorigenesis [Research]
Shp-1 (Src homology region 2 domain-containing protein tyrosine phosphatase-1) is a phosphatase that is highly expressed in hematopoietic and epithelial cells. Whereas its function is largely characterized in hematopoietic cells, its role in epithelial cells, such as intestinal epithelial cells (IECs), is not well known. Here, we generated mice with an IEC-specific knockout of Shp-1 (Src homology region 2 domain–containing phosphatase-1; Shp-1IEC-KO). We showed that the loss of epithelial Shp-1 leads to an intestinalomegaly that is associated with an increase in epithelial cell proliferation and size. Histologic anal...
Source: FASEB Journal - August 1, 2017 Category: Biology Authors: Leblanc, C., Langlois, M.-J., Coulombe, G., Vaillancourt-Lavigueur, V., Jones, C., Carrier, J. C., Boudreau, F., Rivard, N. Tags: Research Source Type: research
Inhibition of inflammasome activation improves lung acute injury induced by carrageenan in a mouse model of pleurisy [Research]
The inflammasome NLRP3 is a molecular pathway activated by a wide range of cellular insults to elicit innate immune defenses through the activation of caspase-1 and the maturation of proinflammatory cytokines, such as IL-1β and IL-18. The expression of NRLP3 is abnormally elevated in numerous human inflammatory diseases, including pulmonary diseases. An injection of carrageenan (CAR) into the pleural cavity triggered an acute inflammatory response, leading to tissue damage, inflammatory exudates, leukocyte infiltration, and increased myeloperoxidase activity. The aim of this study was to assess the effect of the infla...
Source: FASEB Journal - August 1, 2017 Category: Biology Authors: Fusco, R., Gugliandolo, E., Biundo, F., Campolo, M., Di Paola, R., Cuzzocrea, S. Tags: Research Source Type: research
Different expression levels of DLK1 inversely modulate the oncogenic potential of human MDA-MB-231 breast cancer cells through inhibition of NOTCH1 signaling [Research]
NOTCH receptors participate in cancer cell proliferation and survival. Accumulated evidence indicates that, depending on the cellular context, these receptors can function as oncogenes or as tumor-suppressor genes. The epidermal growth factor–like protein delta-like homolog (DLK)1 acts as a NOTCH inhibitor and is involved in the regulation of normal and tumoral growth. In this work, we focused on the role of DLK1 in the control of breast cancer cell growth, a tumor type in which NOTCH receptors have been shown to play both opposite roles. We found that human DLK1 inhibits NOTCH signaling in MDA-MB-231 breast cancer c...
Source: FASEB Journal - August 1, 2017 Category: Biology Authors: Nueda, M.-L., Naranjo, A.-I., Baladron, V., Laborda, J. Tags: Research Source Type: research
Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides [Research]
Gangliosides (sialylated glycolipids) play an essential role in the CNS by regulating recognition and signaling in neurons. Metabolic blocks in processing and catabolism of gangliosides result in the development of severe neurologic disorders, including gangliosidoses manifesting with neurodegeneration and neuroinflammation. We demonstrate that 2 mammalian enzymes, neuraminidases 3 and 4, play important roles in catabolic processing of brain gangliosides by cleaving terminal sialic acid residues in their glycan chains. In neuraminidase 3 and 4 double-knockout mice, GM3 ganglioside is stored in microglia, vascular pericytes...
Source: FASEB Journal - August 1, 2017 Category: Biology Authors: Pan, X., De Aragao, C. D. B. P., Velasco-Martin, J. P., Priestman, D. A., Wu, H. Y., Takahashi, K., Yamaguchi, K., Sturiale, L., Garozzo, D., Platt, F. M., Lamarche-Vane, N., Morales, C. R., Miyagi, T., Pshezhetsky, A. V. Tags: Research Source Type: research
Canonical JAK-STAT signaling is pivotal for long-term depression at adult hippocampal temporoammonic-CA1 synapses [Research]
The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway is involved in numerous cellular processes and it is implicated in neurodegenerative disorders, like Alzheimer disease. Recent studies identified a crucial role for this pathway in activity-dependent long-term depression (LTD) at hippocampal Schaffer collateral (SC)-CA1 synapses. However, it is unclear whether JAK-STAT signaling also regulates excitatory synaptic function at the anatomically distinct temporoammonic (TA) input to CA1 neurons. Here we demonstrate that LTD at adult TA-CA1 synapses involves JAK-STAT signaling, but ...
Source: FASEB Journal - August 1, 2017 Category: Biology Authors: McGregor, G., Irving, A. J., Harvey, J. Tags: Research Source Type: research
NFAT5-sensitive Orai1 expression and store-operated Ca2+ entry in megakaryocytes [Research]
The transcription factor nuclear factor of activated T cells 5 (NFAT5) is up-regulated in several clinical disorders, including dehydration. NFAT5-sensitive genes include serum and glucocorticoid-inducible kinase 1 (SGK1). The kinase is a powerful regulator of Orai1, a Ca2+ channel accomplishing store-operated Ca2+ entry (SOCE). Orai1 is stimulated after intracellular store depletion by the Ca2+ sensors stromal interaction molecule 1 (STIM1), or STIM2, or both. In the present study, we explored whether nuclear factor of activated T cell (NFAT)-5 influences Ca2+ signaling in megakaryocytes. To this end, human megakaryocytic...
Source: FASEB Journal - August 1, 2017 Category: Biology Authors: Sahu, I., Pelzl, L., Sukkar, B., Fakhri, H., al-Maghout, T., Cao, H., Hauser, S., Gutti, R., Gawaz, M., Lang, F. Tags: Research Source Type: research
Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration [Research]
Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism. Recent studies have implicated TH signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we demonstrated that antithyroid drug treatment and targeting iodothyronine deiodinases (DIOs) to suppress cellular tri-iodothyronine (T3) production or increase T3 degradation preserves cones. In this work, we investigated the effectiveness of inhibition of the TH receptor (TR). Two genes, THRA and THRB, encode TRs; THRB2 has been associated with cone viability. Using TR antagonists and Thrb2 deletion, we exami...
Source: FASEB Journal - August 1, 2017 Category: Biology Authors: Ma, H., Yang, F., Butler, M. R., Belcher, J., Redmond, T. M., Placzek, A. T., Scanlan, T. S., Ding, X.-Q. Tags: Research Source Type: research
Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes [Research]
This study defines a mechanism by which Dsg2 expression in cancer cells can modulate the tumor microenvironment, a step critical for tumor progression.—Overmiller, A. M., Pierluissi, J. A., Wermuth, P. J., Sauma, S., Martinez-Outschoorn, U., Tuluc, M., Luginbuhl, A., Curry, J., Harshyne, L. A., Wahl, J. K. III, South, A. P., Mahoney, M. G. Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes. (Source: FASEB Journal)
Source: FASEB Journal - August 1, 2017 Category: Biology Authors: Overmiller, A. M., Pierluissi, J. A., Wermuth, P. J., Sauma, S., Martinez-Outschoorn, U., Tuluc, M., Luginbuhl, A., Curry, J., Harshyne, L. A., Wahl, J. K., South, A. P., Mahoney, M. G. Tags: Research Source Type: research
Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma [Research]
Studies in vitro and in vivo demonstrate that membrane/lipid rafts and caveolin (Cav) organize progrowth receptors, and, when overexpressed specifically in neurons, Cav-1 augments neuronal signaling and growth and improves cognitive function in adult and aged mice; however, whether neuronal Cav-1 overexpression can preserve motor and cognitive function in the brain trauma setting is unknown. Here, we generated a neuron-targeted Cav-1–overexpressing transgenic (Tg) mouse [synapsin-driven Cav-1 (SynCav1 Tg)] and subjected it to a controlled cortical impact model of brain trauma and measured biochemical, anatomic, and b...
Source: FASEB Journal - August 1, 2017 Category: Biology Authors: Egawa, J., Schilling, J. M., Cui, W., Posadas, E., Sawada, A., Alas, B., Zemljic-Harpf, A. E., Fannon-Pavlich, M. J., Mandyam, C. D., Roth, D. M., Patel, H. H., Patel, P. M., Head, B. P. Tags: Research Source Type: research
Biosynthesis of proresolving lipid mediators by vascular cells and tissues [Research]
Recent evidence suggests that specialized proresolving lipid mediators (SPMs) generated from docosahexaenoic acid (DHA) can modulate the vascular injury response. However, cellular sources for these autacoids within the vessel wall remain unclear. Here, we investigated whether isolated vascular cells and tissues can produce SPMs and assessed expression and subcellular localization of the key SPM biosynthetic enzyme 5-lipoxygenase (LOX) in vascular cells. Intact human arteries incubated with DHA ex vivo produced 17-hydroxy DHA (17-HDHA) and D-series resolvins, as assessed by liquid chromatography-tandem mass spectrometry. A...
Source: FASEB Journal - August 1, 2017 Category: Biology Authors: Chatterjee, A., Komshian, S., Sansbury, B. E., Wu, B., Mottola, G., Chen, M., Spite, M., Conte, M. S. Tags: Research Source Type: research
Adeno-associated virus 9-mediated Cdk5 inhibitory peptide reverses pathologic changes and behavioral deficits in the Alzheimers disease mouse model [Research]
Cyclin-dependent kinase 5 (Cdk5), which binds to and is activated by p35, phosphorylates multiple substrates and plays an essential role in the development and function of the CNS; however, proteolytic production of p25 from p35 under stress conditions leads to the inappropriate activation of Cdk5 and contributes to hyperphosphorylation of and other substrates that are related to the pathogenesis of Alzheimer’s disease. Selective inhibition of aberrant Cdk5 activity via genetic overexpression of Cdk5 inhibitory peptide (CIP) reduces pathologic changes and prevents brain atrophy and memory loss in p25-transgenic mice....
Source: FASEB Journal - August 1, 2017 Category: Biology Authors: He, Y., Pan, S., Xu, M., He, R., Huang, W., Song, P., Huang, J., Zhang, H.-T., Hu, Y. Tags: Research Source Type: research
CB1 cannabinoid receptor drives oocyte maturation and embryo development via PI3K/Akt and MAPK pathways [Research]
Endocannabinoids have been recognized as mediators of practically all reproductive events in mammals. However, little is known about the role of this system in oocyte maturation. In a mouse model, we observed that activation of cannabinoid receptor 1 (CB1) during in vitro oocyte maturation modulated the phosphorylation status of Akt and ERK1/2 and enhanced the subsequent embryo production. In the absence of CB1, in vivo oocyte maturation was impaired and embryo development delayed. Cannabinoid receptor 2 (CB2) was unable to rescue these effects. Finally, we confirmed abnormal oocyte maturation rather than impaired embryoni...
Source: FASEB Journal - August 1, 2017 Category: Biology Authors: Lopez-Cardona, A. P., Perez-Cerezales, S., Fernandez-Gonzalez, R., Laguna-Barraza, R., Pericuesta, E., Agirregoitia, N., Gutierrez-Adan, A., Agirregoitia, E. Tags: Research Source Type: research
