Search results for "serine"

Mutant HRAS as novel target for MEK and mTOR inhibitors.

2015

HRAS is a frequently mutated oncogene in cancer. However, mutant HRAS as drug target has not been investigated so far. Here, we show that mutant HRAS hyperactivates the RAS and the mTOR pathway in various cancer cell lines including lung, bladder and esophageal cancer. HRAS mutation sensitized toward growth inhibition by the MEK inhibitors AZD6244, MEK162 and PD0325901. Further, we found that MEK inhibitors induce apoptosis in mutant HRAS cell lines but not in cell lines lacking RAS mutations. In addition, knockdown of HRAS by siRNA blocked cell growth in mutant HRAS cell lines. Inhibition of the PI3K pathway alone or in combination with MEK inhibitors did not alter signaling nor had an imp…

Demonstration of P29, an oestrogen receptor-associated tumor marker, in human term placenta.

1991

A Mr29,000 serine phosphoprotein (P29) related to oestradiol receptor was studied in human term placenta with the use of a specific monoclonal antibody (D5). D5 was used with two different methods, immunohistochemistry and immunoradiometry. For immunohistochemistry, an indirect immunoperoxidase method was chosen to detect P29 in methacarn-fixed, wax-embedded sections. P29 was mostly confined to the syncytiotrophoblast surrounding placental villi, staining being positive in both cytoplasm and nuclei. The stroma of villi was negative. Content of P29 was uniformly high in crude placental cytosol, as measured by immunoradiometry assays. Specificity of D5 against P29 in placenta was tested by an…

Developmental and tumoral vascularization is regulated by G protein-coupled receptor kinase 2

2012

Tumor vessel dysfunction is a pivotal event in cancer progression. Using an in vivo neovascularization model, we identified G protein–coupled receptor kinase 2 (GRK2) as a key angiogenesis regulator. An impaired angiogenic response involving immature vessels was observed in mice hemizygous for Grk2 or in animals with endothelium-specific Grk2 silencing. ECs isolated from these animals displayed intrinsic alterations in migration, TGF-β signaling, and formation of tubular networks. Remarkably, an altered pattern of vessel growth and maturation was detected in postnatal retinas from endothelium-specific Grk2 knockout animals. Mouse embryos with systemic or endothelium-selective Grk2 ablation …

AMP-activated protein kinase (AMPK) signaling pathway: A potential mechanism involved in PAFIYAMA syndrome?

2016

A girl with an atypical form of ataxia telangiectasia and an additional de novo 3.14Mb microduplication in region 19q12

2011

A 9-year-old girl born to healthy parents showed manifestations suggestive of ataxia telangiectasia (AT), such as short stature, sudden short bouts of horizontal and rotary nystagmus, a weak and dysarthric voice, rolling gait, unstable posture, and atactic movements. She did not show several cardinal features typical of AT such as frequent, severe infections of the respiratory tract. In contrast, she showed symptoms not generally related to AT, including microcephaly, profound motor and mental retardation, small hands and feet, severely and progressively reduced muscle tone with slackly protruding abdomen and undue drooling, excess fat on her upper arms, and severe oligoarthritis. A cranial…

Platelet membrane fluidity, platelet membrane lipid pattern and platelet cytosolic Ca2+ content in subjects with vascular atherosclerotic disease

1994

In a group of subjects with vascular atherosclerotic disease (V AD) we examined the platelet membrane fluidity (obtained marking intact resting platelets with TMA-DPH), the platelet membrane cholesteroVphospholipid ratio (CIPL using column chromatography), the platelet membrane individual phospholipids (employing the thin layer chromatography) and the platelet cytosolic Ca2+ content (evaluated marking intact resting platelets with Fura 2-AM). From the obtained data, it is evident that platelet membrane fluidity differentiates normals from V AD subjects. Platelet membrane lipid pattern (CIPL and individual phospholipids) and cytosolic Ca2+ content do not discriminate normals from V AD subjec…

Current insights into the German lipoprotein apheresis standard: PCSK9-inhibitors, lipoprotein apheresis or both?

2017

Abstract According to current European guidelines, lipid lowering therapy for progressive cardiovascular disease including cardiovascular events has to be focused on a target level for LDL-C. In contrast for Lp(a) a threshold has to be defined with respect to the method of measurement. However, due to new lipid lowering drug developments like PCSK9-inhibitors (PCSK-9-I) a therapeutic algorithm for patients with severe hypercholesterolemia or isolated Lipoprotein(a)-hyperlipoproteinemia with progressive cardiovascular disease may be necessary to manage the use of PCSK9-I, lipoprotein apheresis (LA) or both. The therapeutic approach for patients with homozygous familial hypercholesterolemia i…

Growth and differentiation factor 11 (GDF11): Functions in the regulation of erythropoiesis and cardiac regeneration

2015

International audience; Members of the TGF-β superfamily transduce their signals through type I and II receptor serine/threonine kinases. The binding of activins to activin type IIA (ActRIIA) or type IIB (ActRIIB) receptors induces the recruitment and phosphorylation of an activin type I receptor (ALK4 and/or ALK7), which then phosphorylates the Smad2 and Smad3 intracellular signaling proteins. The regulation of members of the TGF-β family is known to be complex, because many proteins able to bind the ligands and inhibit their activities have been identified. Growth and differentiation factor 11 (Gdf11) belongs to the TGF-β family. GDF11, like other members of the TGF-β superfamily, is prod…

Chemosensory signalling pathways involved in sensing of amino acids by the ghrelin cell

2015

AbstractTaste receptors on enteroendocrine cells sense nutrients and transmit signals that control gut hormone release. This study aimed to investigate the amino acid (AA) sensing mechanisms of the ghrelin cell in a gastric ghrelinoma cell line, tissue segments and mice. Peptone and specific classes of amino acids stimulate ghrelin secretion in the ghrelinoma cell line. Sensing of L-Phe occurs via the CaSR, monosodium glutamate via the TAS1R1-TAS1R3 while L-Ala and peptone act via 2 different amino acid taste receptors: CaSR & TAS1R1-TAS1R3 and CaSR & GPRC6A, respectively. The stimulatory effect of peptone on ghrelin release was mimicked ex vivo in gastric but not in jejunal tissue …

Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1-PP2A protein complex.

2012

Expansion of CAG repeats is a common feature of various neurodegenerative disorders, including Huntington's disease. Here we show that expanded CAG repeats bind to a translation regulatory protein complex containing MID1, protein phosphatase 2A and 40S ribosomal S6 kinase. Binding of the MID1-protein phosphatase 2A protein complex increases with CAG repeat size and stimulates translation of the CAG repeat expansion containing messenger RNA in a MID1-, protein phosphatase 2A- and mammalian target of rapamycin-dependent manner. Our data indicate that pathological CAG repeat expansions upregulate protein translation leading to an overproduction of aberrant protein and suggest that the MID1-com…