Protein Kinase AMP-Activated Catalytic Subunit Alpha 1 (PRKAA1) knockdown effect on the transcriptome of primary human acute myeloid leukemia (AML) cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE114105 | GEO | 2018/06/01
REPOSITORIES: GEO
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Project description:Protein Kinase AMP-Activated Catalytic Subunit Alpha 1 (PRKAA1) knockdown effect on the transcriptome of primary human acute myeloid leukemia (AML) cells
| PRJNA464341 | ENA
Project description:AMP-activated protein 1 kinase (AMPK), a phylogenetically conserved serine/threonine kinase regarded as a key cellular energy sensor, exists in eukaryotes as a heterotrimer comprising a catalytic α and regulatory β and γ subunits. In humans, activating mutations in the gene encoding the γ2 subunit of AMPK (PRKAG2) display a cardiac phenotype of left ventricular hypertrophy (LVH), conduction system disease, ventricular pre-excitation and increased cardiomyocyte glycogen accumulation. While existing transgenic models have elucidated the pathogenesis of several aspects of the disease5-7, the slow heart rate (sinus bradycardia) – a prominent feature of the disease – remains poorly understood. Here, using gene-targeting to generate mice which recapitulate this bradycardia, we demonstrate that γ2 AMPK activation perturbs fundamental mechanisms that determine sinoatrial pacemaker cell function. Reduction in the sarcolemmal hyperpolarization activated (“funny”) current (If) and damping of ryanodine receptor-derived diastolic local subsarcolemmal Ca2+ releases (LCRs)12,13 contribute to reduced sinoatrial cell spontaneous activity and, ultimately, to a lower heart rate. Pharmacological activation of AMPK reversibly reduces the beating rate of murine pluripotent stem cell-derived induced sinoatrial bodies. In contrast, using a mouse knock-out of γ2 AMPK, which exhibits an increased heart rate, we demonstrate a role for γ2 AMPK in physiological heart rate regulation, including an indispensable role in the bradycardic adaptation to endurance exercise. Through regulating the cardiac pacemaker and thereby heart rate, γ2 AMPK by virtue of its energy-sensing role, is a key physiological determinant of overall cardiac energy homeostasis.
2017-09-30 | GSE73047 | GEO
Project description:Mouse rod photoreceptor specific Prkaa1 knockouts were isolated from retinas and processed for phosphoproteomics to elucidate downstream kinase targets. Prkaa1 is one of the isoforms for the catalytic subunit of AMP-activated protein kinase (AMPK), an essential nutrient sensing enzyme responsible for maintaining many metabolic processes.
2024-06-16 | PXD045667 | Pride
Project description:The conserved Snf1/AMPK (AMP-activated protein Kinase) family is one of the central components in nutrient sensing and regulation of carbon metabolism in eukaryotes. It is also involved in several other processes such as stress resistance, invasive growth and ageing. Snf1 kinase is composed of a catalytic alpha-subunit Snf1, a regulatory gamma-subunit Snf4 and one of three possible beta-subunits, Sip1, Sip2 or Gal83. We used a systematic approach to study the role of the three beta-subunits by analyzing all 7 possible combinations of beta-subunit deletions together with the reference strain.
2010-05-27 | E-GEOD-20591 | biostudies-arrayexpress
Project description:Long non-coding RNAs (lncRNA) and circular RNAs (circRNA) that sponge miRNAs could indirectly regulate gene expression, contributing to certain biological processes. This study aimed to investigate the role of non-coding RNAs in the pathogenesis of myocardial ischemia reperfusion-injury (MIRI). MIRI in male C57B/6J mice was induced by left anterior descending coronary artery ligation occlusion for 30 min, and 4 h of reperfusion. RNA sequencing was performed to obtain the mRNA and non-coding RNA expression profiles of the MIRI and sham groups. Bioinformatic methods were used to analyze the co-expression RNAs, miRNA binding sites and competitive endogenous RNA (ceRNA) pairs. Differentially expressed RNAs were identified with a cutoff fold change > 2 and p < 0.05. A total of 64 mRNAs were upregulated and 98 mRNAs were downregulated, and 10 lncRNAs were upregulated and 10 lncRNAs were downregulated. All altered (p < 0.05) mRNAs were selected for gene ontology and pathway analysis. The AMP-activated protein kinase (AMPK) signaling pathway was enriched in the downregulated genes, and the activation of AMPK was confirmed by Western blotting. The lncRNA co-expression network and ceRNA network base on genes in AMPK signaling pathway were then constructed, revealing that ENSMUST00000147762.7 and TUCP_000184 might be key regulators in MIRI induced AMPK activation. The expression levels of AMPK signaling-related RNAs and those involved in the ceRNA network were validated using qRT-PCR. Overall, this study identified potential new targets on AMPK signaling in MIRI.
2024-04-01 | GSE240842 | GEO
Project description:The yeast Snf1p/AMP-activated kinase (AMPK) maintains energy homeostasis, controlling metabolic processes and glucose derepression in response to nutrient levels and environmental cues. Under conditions of nitrogen or glucose limitation, Snf1p regulates pseudohyphal growth, a morphological transition characterized by the formation of extended multicellular filaments. During pseudohyphal growth, Snf1p is required for wild-type levels of inositol polyphosphate (InsP), soluble phosphorylated species of the six-carbon cyclitol inositol that function as conserved metabolic second messengers. InsP levels are established through the activity of a family of inositol kinases, including the inositol polyphosphate kinase Kcs1p, which principally generates pyrophosphorylated forms of InsP7 and InsP8. Here, we report that Snf1p regulates Kcs1p, affecting Kcs1p phosphorylation and inositol kinase activity. A snf1 kinase-defective mutant exhibits decreased Kcs1p phosphorylation, and Kcs1p is phosphorylated in vivo at Ser residues 537 and 646 during pseudohyphal growth. By in vitro analysis, Snf1p directly phosphorylates Kcs1p, predominantly at amino acids 537 and 646. A yeast strain carrying kcs1 encoding Ser-to-Ala point mutations at these residues (kcs1-S537A,S646A) shows elevated levels of pyrophosphorylated InsP7, comparable to InsP7 levels observed upon deletion of SNF1. The kcs1-S537A,S646A mutant exhibits decreased pseudohyphal growth, invasive growth, and cell elongation. Transcriptional profiling indicates extensive perturbation of metabolic pathways in kcs1-S537A,S646A. Growth of kcs1-S537A,S646A is affected on medium containing glycerol and antimycin A, consistent with decreased Snf1p signaling. This work identifies Snf1p phosphorylation of Kcs1p, collectively highlighting the interconnectedness of AMPK activity and InsP signaling in coordinating nutrient availability, energy homoeostasis, and cell growth.
2024-01-10 | GSE246711 | GEO
Project description:The cyclic AMP-protein kinase A pathway has a central role in the biology of Candida albicans, a prominent fungal pathogen of humans. The two catalytic subunits for cyclic AMP-dependent protein kinase, Tpk1 (orf19.4892) and Tpk2 (orf19.2277), have divergent roles, and most studies indicate a more pronounced role for Tpk2. Here we dissect two Tpk1-responsive properties: adherence and cell wall integrity. Homozygous tpk1/tpk1 mutants are hyperadherent, and a Tpk1 defect enables biofilm formation in the absence of Bcr1, a central transcriptional regulator of biofilm adhesins. Microarray analysis revealed an enrichment for cell wall and surface functions among Tpk1-repressed genes, and overexpression of individual target genes indicates that cell surface proteins Als1, Als2, Als4, Csh1, and Csp37 contribute to Tpk1-regulated adherence. Tpk1 is also required for cell wall integrity, but has no role in the cell wall integrity gene expression response. Interestingly, increased expression of the adhesin gene ALS2 conferred a cell wall defect, as manifested in hypersensitivity to the cell wall inhibitor caspofungin and a shallow cell wall structure. Our findings indicate that Tpk1 has a central role in C. albicans cell wall properties that is exerted through repression of select cell surface protein genes. Two-color microarrays using a closed-loop experimental design to determine the effects of a M-bM-^HM-^Ftpk1 deletion in the absence or presence of the antifungal Caspofungin (CF)
2012-08-06 | E-GEOD-38846 | biostudies-arrayexpress
Project description:Altered metabolism fuels two hallmark properties of cancer cells, unlimited proliferation and differentiation blockade. AMP-activated protein kinase (AMPK) is a master regulator of bioenergetics crucial for glucose metabolism in acute myeloid leukemia (AML) and its inhibition delays leukemogenesis, but whether the metabolic function of AMPK alters AML epigenome remains unknown. Here, we demonstrate that AMPK maintains the epigenome of MLL-rearranged AML by linking acetyl-CoA homeostasis to BET bromodomain protein recruitment to chromatin. AMPK deletion reduced acetyl-CoA and histone acetylation, displacing BET proteins from chromatin in leukemia-initiating cells (LICs). In both mouse and patient-derived xenograft AML models, treating with AMPK and BET inhibitors synergistically suppressed AML. Our results provide a therapeutic rationale to target AMPK and BET for AML therapy.
2019-09-05 | GSE128000 | GEO
Project description:Altered metabolism fuels two hallmark properties of cancer cells, unlimited proliferation and differentiation blockade. AMP-activated protein kinase (AMPK) is a master regulator of bioenergetics crucial for glucose metabolism in acute myeloid leukemia (AML) and its inhibition delays leukemogenesis, but whether the metabolic function of AMPK alters AML epigenome remains unknown. Here, we demonstrate that AMPK maintains the epigenome of MLL-rearranged AML by linking acetyl-CoA homeostasis to BET bromodomain protein recruitment to chromatin. AMPK deletion reduced acetyl-CoA and histone acetylation, displacing BET proteins from chromatin in leukemia-initiating cells (LICs). In both mouse and patient-derived xenograft AML models, treating with AMPK and BET inhibitors synergistically suppressed AML. Our results provide a therapeutic rationale to target AMPK and BET for AML therapy.
2019-09-05 | GSE127999 | GEO
Project description:During aging, the loss of metabolic homeostasis drives a myriad of pathologies. A central regulator of cellular energy, the AMP-activated protein kinase (AMPK), orchestrates organismal metabolism. However, direct genetic manipulations of the AMPK complex in mice have, so far, produced detrimental phenotypes. Here, as an alternative approach, we alter energy homeostasis by manipulating the upstream nucleotide pool. Using the turquoise killifish, we mutate APRT, a key enzyme in AMP biosynthesis, and extend the lifespan of heterozygous males. Next, applying an integrated omics approach identify that metabolic functions are rejuvenated in old mutants, which also display a fasting-like metabolic profile and resistance to high-fat diet. On the cellular level, heterozygous cells exhibit enhanced nutrient sensitivity, reduced ATP levels, and AMPK ¬activation. Finally, lifelong intermittent fasting abolishes the longevity benefits. Our findings suggest that perturbing AMP biosynthesis may modulate vertebrate lifespan, and propose APRT as a promising target for promoting metabolic health.
2023-05-23 | GSE190757 | GEO