Kinase AMP-activated Catalytic Subunit Alpha Research Articles

PRKAA1 (protein kinase AMP-activated catalytic subunit alpha 1)

PRKAA1 (protein kinase AMP-activated catalytic subunit alpha 1)

848 Genes implicated in lipid & metabolic regulation downregulated in CCCA

Central centrifugal cicatricial alopecia (CCCA) is the most common form of scarring hair loss in black women. It is characterized by fibrosis out of proportion to the clinical and histologic signs of inflammation, which may lead to progressive end stage fibrosis. Previous work by our group showed that affected CCCA scalp is characterized by an increased expression of profibrotic genes seen in other conditions of aberrant scarring, including hepatic fibrosis. While the cause of this fibrosis is unknown, downregulation of adenosine monophosphate activated protein kinase (AMPK) have been implicated as a primary mediator of hepatic fibrosis, as well as other conditions of scarring. Furthermore, disruption in fatty acid metabolism, including linoleic acid, has been implicated in excess fibrosis including enhanced proliferation of fibroblasts and collagen type I. We performed gene expression microarrays on paired affected and unaffected scalp samples in five patients with CCCA to understand the role of metabolic dysregulation on the pathogenesis of CCCA. Transcriptome-wide analysis of over 20,000 human genes was performed, analyzing all known exons and the 200 (0.9%) most downregulated genes based on fold change were identified. We revealed widespread alterations of genes regulating lipid metabolism (p=2.3 x 10-3) and fatty acid biosynthesis (p=5.3 x 10-6) genes. In particular, the mRNA transcript of protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2), which partially encodes for the a subunit of AMPK, was shown to be downregulated by 34% in our CCCA affected scalp compared to the unaffected scalp (p=6.4 x 10-3). Linoleic acid metabolism was also disproportionately dysregulated in our dataset (p=9.1 x 10-3). Our work signifies a potential role that metabolic dysregulation may play in the pathogenesis of CCCA.

Regorafenib induces lethal autophagy arrest by stabilizing PSAT1 in glioblastoma

ABSTRACTGBM (glioblastoma multiforme) is the most common and aggressive brain tumor with no curative options available. Therefore, it is imperative to develop novel potent therapeutic drugs for GBM treatment. Here, we show that regorafenib, an oral multi-kinase inhibitor, exhibits superior therapeutic efficacy over temozolomide, the first-line chemotherapeutic agent for GBM treatment both in vitro and in vivo. Mechanistically, regorafenib directly stabilizes PSAT1 (phosphoserine aminotransferase 1), a critical enzyme for serine synthesis, to trigger PRKAA-dependent autophagy initiation and inhibit RAB11A-mediated autophagosome-lysosome fusion, resulting in lethal autophagy arrest in GBM cells. Maintenance of PSAT1 at a high level is essential for regorafenib-induced GBM suppression. Together, our data provide novel mechanistic insights of regorafenib-induced autophagy arrest and suggest a new paradigm for effective treatment of GBM.Abbreviations: 3-MA: 3-methyladenine; ACACA: acetyl coenzyme A carboxylase alpha; ACTB/β-actin: actin, beta; AMPK: adenosine monophosphate-activated protein kinase; ATG5: autophagy related 5; CTSD: cathepsin D; DN-: dominant-negative; GBM: glioblastoma multiforme; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PSAT1: phosphoserine aminotransferase 1; SQSTM1/p62: sequestosome 1; TKIs: tyrosine kinase inhibitors.

Sodium tanshinone IIA sulfonate ameliorates hepatic steatosis by inhibiting lipogenesis and inflammation

Non-alcoholic fatty liver disease (NAFLD) is becoming an epidemic disease in adults and children worldwide. Importantly, there are currently no approved treatments available for NAFLD. This study aims to investigate the potential applications of sodium tanshinone IIA sulfonate (STS) on improving the NAFLD condition using both in vitro and in vivo approaches. The results showed that STS markedly inhibited lipid accumulation in oleic acid (OA) and palmitic acid (PA) treated HepG2 and primary immortalized human hepatic (PIH) cells. STS suppressed lipogenesis by inhibiting expression of sterol regulatory element binding transcription factor 1 (SREBF1), fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD). In addition, STS reduced inflammation in cells treated with OA-PA, shown by decreased transcriptional levels of tumor necrosis factor (TNF), transforming growth factor beta 1 (TGFB1) and interleukin 1 beta (IL1B). Consistently, protective effects on hepatic steatosis in db/db mice were observed after STS administration, demonstrated by decreased lipid accumulation in mouse hepatocytes. This protective effect might be associated with STS induced activation of sirtuin 1 (SIRT1)/protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1) pathways. Our findings suggest a potential therapeutic role for STS in the treatment of NAFLD.

Analysis of miRNA-seq in the liver of common carp (Cyprinus carpio L.) in response to different environmental temperatures.

Water temperature affects the survival, growth, immunity, reproduction, and productivity of farmed fish. The temperature beyond suitable range will disrupt the normal physiological activity. Common carp (Cyprinus carpio L.) is a representative eurythermic fish; they are able to sense and respond to changes in water temperature by adjusting their physiology. To investigate the miRNAs in common carp at different temperatures, nine liver small-RNA libraries (5°C, 17°C, and 30°C, each group have three biological repetitions) were constructed and sequenced using high-throughput sequencing. A total of 110 known miRNAs were identified. Twenty-nine known miRNAs were differentially expressed compared with in control group. GO and KEGG analysis indicated that the miRNAs may play important roles in metabolism and environment information processing. Specifically, we considered the insulin-signaling and glycerophospholipid metabolism pathway, and the results show that in 30°C, miR-301a, miR-203b-5p, and miR-210-3p were upregulated; their target genes which are the mechanistic targets of the rapamycin kinase (mtor) gene and the protein kinase AMP-activated catalytic subunit alpha 1 (prkaa1) gene in the insulin-signaling pathway were downregulated. And miR-9-5p, miR-27d, miR-92b-3p, and miR-155 were upregulated; their target genes, 1-acylglycerol-3-phosphate O-acyltransferase 3 (agpat3), CDP-diacylglycerol-inositol 3-phosphatidyltransferase (cdipt), glycerol-3-phosphate acyltransferase mitochondrial (gpam), and phosphatidylglycerophosphate synthase 1 (pgs1), in glycerophospholipid metabolism pathway were downregulated. But in 5°C, the situation was opposite. These findings suggest that significant changes occur in energy metabolism and metabolic processes with components of the cell membrane in different temperatures, which significantly advance our understanding of the regulatory mechanisms underlying the physiological change of temperature stress-induced in liver, specifically with regard to miRNAs. These data provide a foundation for further studies of the role of miRNAs in environmental adaptation in fish.

Role of miRNAs in skeletal muscle aging.

PurposeThe aim of this study was to explore the role of miRNAs in the process of skeletal muscle aging.Materials and methodsWe analyzed the miRNA microarray datasets from 19 young and 17 old skeletal muscle samples by bioinformatic analysis. Differentially expressed miRNAs were identified, followed by function and pathway enrichment analysis. The expression of miRNAs were validated by real-time quantitative PCR (RT-qPCR) analysis.ResultsA total of 23 miRNAs were found to be differentially expressed in old muscle samples based on two platforms. Gene targets of upregulated miRNAs were significantly enriched in the oxytocin signaling pathway, AMP-activated protein kinase (AMPK) signaling pathway, and Notch signaling pathway. The target genes of downregulated miRNAs were significantly related to gap junction, salivary secretion, and estrogen signaling pathway. has-miR-19a and hsa-miR-34a were significant nodes in the miRNA regulatory network. has-miR-19a was closely related to the AMPK signaling pathway. hsa-miR-34a was closely related to cellular senescence and mitogen-activated protein kinase (MAPK) signaling pathway. PCR analysis showed that the expression of has-miR-34a-5p and has-miR-449b-5p was significantly higher in the patient group than in the control group, while no significant difference was observed in the expression of has-miR-19a-3p and has-miR-144-3p between the two groups. Furthermore, the expression of key target genes involved in cellular senescence (sirtuin 1 [SITRI]), MAPK signaling pathway (vascular endothelial growth factor A [VEGFA]), and AMPK signaling pathway (protein kinase AMP-activated catalytic subunit alpha 1 [PRKAA1] and 6-phosphofructo-2-kinase/fructose-2-,6-biphosphatase 3 [PFKFB3]) were significantly increased in patients with sarcopenia.Conclusionhas-miR-19a and hsa-miR-34a may play regulatory roles in the aging process of skeletal muscles and may be candidate targets to prevent muscle aging. Further experimental validations are warranted.

P2RX7-MAPK1/2-SP1 axis inhibits MTOR independent HSPB1-mediated astroglial autophagy

Recently, we have reported that heat shock protein B1 (HSPB1) and purinergic receptor P2X7 (P2RX7) are involved in astroglial autophagy (clasmatodendrosis), following status epilepticus (SE). However, the underlying mechanisms of astroglial autophagy have not been completely established. In the present study, we found that the lacking of P2rx7 led to prolonged astroglial HSPB1 induction due to impaired mitogen-activated protein kinase 1/2 (MAPK1/2)-mediated specificity protein 1 (SP1) phosphorylation, following kainic acid-induced SE. Subsequently, the upregulated HSPB1 itself evoked ER stress and exerted protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1, AMPK1)/unc-51 such as autophagy activating kinase 1 (ULK1)- and AKT serine/threonine kinase 1 (AKT1)/glycogen synthase kinase 3 beta (GSK3B)/SH3-domain GRB2-like B1 (SH3GLB1)-mediated autophagic pathways, independent of mechanistic target of rapamycin (MTOR) activity in astrocytes. These findings provide a novel purinergic suppression mechanism to link chaperone expression to autophagy in astrocytes. Therefore, we suggest that P2RX7 may play an important role in the regulation of autophagy by the fine-tuning of HSPB1 expression.

A novel polymorphism in protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) is associated with type 2 diabetes in the Han Chinese population.

It has been proposed that the energy-sensing enzyme AMP-activated protein kinase (AMPK) is a key agent in the pathophysiology of type 2 diabetes mellitus (T2DM). The gene encoding protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) is located at one of the Asian T2DM loci (1p32). Therefore, the aim of the present study was to test for the association of common variants in PRKAA2 with T2DM in the Han Chinese population. We genotyped 221 T2DM patients and 111 controls to assess possible associations of two tagging single nucleotide polymorphisms (tSNPs) in the PRKAA2 gene with T2DM. The clinical characteristics of T2DM cases compared with controls differed significantly. No significant association was observed with the rs2143754 polymorphism whereas the rs2746342 polymorphism exhibited a highly significant association with T2DM. Fasting plasma glucose (FPG) of subjects carrying the G/G genotype of the rs2746342 polymorphism was higher than that of subjects carrying the T allele (P = 0.0049). These associations were magnified in the presence of the G/G genotype of the rs2143754 polymorphism. The rs2746342 polymorphism is significantly associated with susceptibility to T2DM and seems to interact with the rs2143754 polymorphism in the modulation of FPG in the Han Chinese population.

Risk prediction for early-onset gastric carcinoma: a case-control study of polygenic gastric cancer in Han Chinese with hereditary background.

Recent genomewide studies have identified several germline variations associated with gastric cancer. The aim of the present study was to identify, in a Chinese Han population, the individual and combined effects of those single nucleotide polymorphisms (SNPs) that increase the risk of early-onset gastric cancer. We conducted a case-control study comprising 116 patients with gastric cancer as well as 102 sex- and age-matched controls and confirmed that the SNPs MUC1 (mucin 1) rs9841504 and ZBTB20 (zinc finger and BTB domain containing 20) rs4072037 were associated with an increased gastric cancer risk. Of the 116 patients diagnosed with cancer, 65 had at least 1 direct lineal relative with carcinoma of the digestive system or breast/ovarian cancer. These 65 had another 4 SNPs associated with gastric cancer susceptibility: PSCA (prostate stem cell antigen) rs2294008, PLCE1 (phospholipase C epsilon 1) rs2274223, PTGER4/PRKAA1 (prostaglandin E receptor 4/protein kinase AMP-activated catalytic subunit alpha 1) rs13361707, and TYMS (thymidylate synthetase) rs2790. However, each of these low-penetrance susceptibility polymorphisms alone is not considered influential enough to predict the absolute risk of early-onset gastric cancer. Thus we decided to study different combinations of polygenes as they affected for our population. Those subjects with both the risk alleles MUC1 rs9841504 and ZBTB20 rs4072037 had a greater than 3-fold increased risk of gastric cancer. Also those with a hereditary background including the risk alleles PLCE1 rs2274223 and PTGER4/PRKAA1 rs13361707 were 3 times more susceptible to cardia cancer than those without. These findings show that the study of combined polymorphisms, instead of single low-penetrance variations in susceptibility, may lead to a high-risk classification for a specific population.