As normal cells progress toward malignancy, they must switch to an angiogenic phenotype to attract the nourishing vasculature that they depend on for their growth. In cultured fibroblasts from Li-Fraumeni patients, this switch was found to coincide with loss of the wild-type allele of the p53 tumor suppressor gene and to be the result of reduced expression of thrombospondin-1 (TSP-1), a potent inhibitor of angiogenesis. Transfection assays revealed that p53 can stimulate the endogenous TSP-1 gene and positively regulate TSP-1 promoter sequences. These data indicate that, in fibroblasts, wild-type p53 inhibits angiogenesis through regulation of TSP-1 synthesis.

https://science.sciencemag.org/content/sci/265/5178/1582.full.pdf

Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1

In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium

Tumor necrosis factor–α (TNF-α) is a major mediator of both acute and chronic inflammatory responses in many diseases. Tristetraprolin (TTP), the prototype of a class of Cys-Cys-Cys-His (CCCH) zinc finger proteins, inhibited TNF-α production from macrophages by destabilizing its messenger RNA. This effect appeared to result from direct TTP binding to the AU-rich element of the TNF-α messenger RNA. TTP is a cytosolic protein in these cells, and its biosynthesis was induced by the same agents that stimulate TNF-α production, including TNF-α itself. These findings identify TTP as a component of a negative feedback loop that interferes with TNF-α production by destabilizing its messenger RNA. This pathway represents a potential target for anti–TNF-α therapies.

https://science.sciencemag.org/content/sci/281/5379/1001.full.pdf

Feedback Inhibition of Macrophage Tumor Necrosis Factor-α Production by Tristetraprolin

The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress.

The amiloride-sensitive epithelial sodium channel, ENaC, is a heteromultimeric protein made up of three homologous subunits (alpha, beta and gamma) (1,2). In vitro, assembly and expression of functional active sodium channels in the Xenopus oocyte is strictly dependent on alpha-ENaC--the beta and gamma subunits by themselves are unable to induce an amiloride-sensitive sodium current in this heterologous expression system (2). In vivo, ENaC constitutes the limiting step for sodium absorption in epithelial cells that line the distal renal tubule, distal colon and the duct of several exocrine glands. The adult lung expresses alpha, beta and gamma ENaC (3,4), and an amiloride-sensitive electrogenic sodium reabsorption has been documented in upper and lower airways (3-7), but it is not established whether this sodium transport is mediated by ENaC in vivo. We inactivated the mouse alpha-ENaC gene by gene targeting. Amiloride-sensitive electrogenic Na+ transport was abolished in airway epithelia from alpha-ENaC(-/-) mice. Alpha-ENaC(-/-) neonates developed respiratory distress and died within 40 h of birth from failure to clear their lungs of liquid. This study shows that ENaC plays a critical role in the adaptation of the newborn lung to air breathing.

Early death due to defective neonatal lung liquid clearance in alpha-ENaC-deficient mice

Full length cDNAs encoding the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from rat and man have been isolated and sequenced. Many GAPDH gene-related sequences have been found in both genomes based on genomic blot hybridization analysis. Only one functional gene product is known. Results from genomic library screenings suggest that there are 300-400 copies of these sequences in the rat genome and approximately 100 in the human genome. Some of these related sequences have been shown to be processed pseudogenes. We have isolated several rat cDNA clones corresponding to these pseudogenes indicating that some pseudogenes are transcribed. Rat and human cDNAs are 89% homologous in the coding region, and 76% homologous in the first 100 base pairs of the 3'-noncoding region. Comparison of these two cDNA sequences with those of the chicken, Drosophila and yeast genes allows the analysis of the evolution of the GAPDH genes in detail.

/pdf/isolation-and-characterization-of-rat-and-human-454z5flfxe.pdf

Isolation and characterization of rat and human glyceraldehyde-3-phosphate dehydrogenase cDNAs: genomic complexity and molecular evolution of the gene

One of the genes encoding glyceraldehyde 3-phosphate dehydrogenase of Drosophila melanogaster, Gapdh-2, is expressed in all cell types examined, but its level of expression is regulated developmentally. Here we report the analysis of the regulatory sequences for the transcription of Gapdh-2. We have generated Gapdh-2-LacZ fusion genes in which the 5'-flanking sequence of Gapdh-2 has been mutated. Examination of the expression of these fusion genes, which have been introduced by transfection into the Schneider II cell line and by germ-line transformation into flies, led to the identification of two distinct regulatory regions, URS-1 and URS-2, within the first 145 bp of the 5'-flanking sequence of Gapdh-2. URS-1 activates transcription throughout the development of Drosophila. However, URS-2 exhibits a dual function during the development. It clearly represses transcription in Schneider II cells, and perhaps also in mid-stage embryos. In contrast, it activates transcription in larvae and adult flies. Thus, URS-2 plays a key role in the developmental regulation of Gapdh-2. Additionally, the efficient transcription of Gapdh-2 in larval and adult stages appears to depend on a synergistic function of URS-1 and URS-2.

/pdf/the-positive-and-negative-transcriptional-regulation-of-the-4dmnva77i2.pdf

The positive and negative transcriptional regulation of the Drosophila Gapdh-2 gene.

Reduction of mtDNA heteroplasmy in mitochondrial replacement therapy by inducing forced mitophagy

Mn3O4 Nanoparticles In Situ Embedded in TiO2 for High-Performance Na-ion capacitor: Balance between 3D Ordered Hierarchically Porous Structure and Heterostructured Interfaces

Xiao Hong Sun

Papers

Isolation and characterization of rat and human glyceraldehyde-3-phosphate dehydrogenase cDNAs: genomic complexity and molecular evolution of the gene

The positive and negative transcriptional regulation of the Drosophila Gapdh-2 gene.

Reduction of mtDNA heteroplasmy in mitochondrial replacement therapy by inducing forced mitophagy

Mn3O4 Nanoparticles In Situ Embedded in TiO2 for High-Performance Na-ion capacitor: Balance between 3D Ordered Hierarchically Porous Structure and Heterostructured Interfaces

Carbon host pore structure regulation boosting fast and stable Se-K electrochemistry towards Se-K ion capacitors