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HPMR

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protein kinase AMP-activated catalytic subunit alpha 2 OKDB#: 2886
 Symbols: PRKAA2 Species: human
 Synonyms: AMPK, AMPK2, PRKAA, AMPKa2  Locus: 1p32.2 in Homo sapiens


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General Comment NCBI Summary: The protein encoded by this gene is a catalytic subunit of the AMP-activated protein kinase (AMPK). AMPK is a heterotrimer consisting of an alpha catalytic subunit, and non-catalytic beta and gamma subunits. AMPK is an important energy-sensing enzyme that monitors cellular energy status. In response to cellular metabolic stresses, AMPK is activated, and thus phosphorylates and inactivates acetyl-CoA carboxylase (ACC) and beta-hydroxy beta-methylglutaryl-CoA reductase (HMGCR), key enzymes involved in regulating de novo biosynthesis of fatty acid and cholesterol. Studies of the mouse counterpart suggest that this catalytic subunit may control whole-body insulin sensitivity and is necessary for maintaining myocardial energy homeostasis during ischemia. [provided by RefSeq, Jul 2008]
General function Enzyme
Comment
Cellular localization Cytoplasmic
Comment
Ovarian function Initiation of primordial follicle growth, Steroid metabolism
Comment Stimulation of ovarian follicle growth following AMPK inhibition. Lu X et al. (2017) Previous studies showed that the protein kinase B (Akt)-mammalian target of rapamycin (mTOR) and Hippo signaling-Yes associated protein (YAP) pathways play important roles in promoting follicle growth. Additionally, other studies demonstrated that 5' adenosine monophosphate-activated protein kinase (AMPK) is an upstream regulatory element of mTOR and YAP. Here, we used AMPK inhibitor (Compound C) to in vitro culture ovaries from 10-day-old mice followed by in vivo grafting into adult hosts, or to in situ treat ovaries of 3-week-old mice by intrabursal injection followed by gonadotropin stimulation. We found the phosphorylation of ovarian mTOR and downstream proteins ,ribosomal protein S6 (S6), and eukaryotic translation-initiation factor 4B (eIF4B) was upregulated following Compound C administration, whereas tuberous sclerosis complex 2 (TSC2) phosphorylation was downregulated. Additionally, treatment with Compound C increased hypoxia-inducible factor 1-alpha (Hif1a), vascular endothelial growth factor A (Vegfa), VEGF receptor 2 (Vegfr2), and connective-tissue growth factor (Ctgf) mRNA levels. Furthermore, treatment of 10-day-old mice with Compound C promoted the growth of preantral and antral follicles accompanied by enhanced angiogenesis. In situ intrabursal injection with Compound C, followed by controlled ovarian hyperstimulation, increased the number of ovulated oocytes in 3-week-old mice, and these oocytes could be successfully fertilized, leading the delivery of healthy pups. Our results demonstrated that treatment with AMPK inhibitor resulted in activation of the mTOR-signaling pathway, increases in Ctgf expression in mouse ovaries, stimulation of follicle development, and promotion of ovarian angiogenesis for ovary growth.////////////////// AMPK regulates progesterone secretion in rat granulosa cells Tosca L, et al . The AMP-activated protein kinase (AMPK) is a major regulator of energy metabolism involved in fatty acid and cholesterol synthesis. In the ovary, cholesterol plays a key role in steroid production. We report the presence of AMPK in rat ovaries and we have investigated its role in granulosa cells. We show using RT-PCR and western-blot that the mRNAs for the alpha1/2 and beta1/2 subunits and the proteins are found in the ovaries. Immunohistochemistry localized the alpha1 AMPK subunit in granulosa cells, corpus luteum, oocyte, and less abundantly in theca cells. Treatment with AICAR (5-amino-imidazole-4-carboxyamide-1-beta-D-ribofuranoside, 1 mM), an activator of AMPK, increased dose-dependent and time-dependent phosphorylation of AMPKalpha1 on Thr 172 in primary granulosa cells. Simultaneously, phosphorylation of Acetyl-CoA Carboxylase at Ser-79 was also increased. AICAR treatment for 48 h halved progesterone secretion, 3beta-HSD protein and mRNA levels and phosphorylation of both basal MAPK ERK1/2 and p38 and in response to IGF-1 and/or FSH in granulosa cells. AICAR treatment (1 mM) had no detectable effect on basal and FSH- and/or IGF-1-induced estradiol production and on granulosa cell proliferation or viability. Adenovirus-mediated expression of dominant negative AMPK totally abolished the effects of AICAR on progesterone secretion, 3beta-HSD protein production, and MAPK ERK1/2 and p38 phosphorylation. Moreover, we showed using specific inhibitors of ERK1/2 and p38 MAPK that the MAPK ERK1/2 and not p38 is involved in progesterone secretion and 3beta-HSD expression, strongly suggesting that the activation of AMPK in response to AICAR reduces progesterone production through the MAPK ERK1/2 signaling pathway in rat granulosa cells.
Expression regulated by
Comment
Ovarian localization Oocyte, Granulosa, Luteal cells
Comment
Follicle stages Antral, Preovulatory, Corpus luteum
Comment
Phenotypes
Mutations 0 mutations
Genomic Region show genomic region
Phenotypes and GWAS show phenotypes and GWAS
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created: July 20, 2005, 2:34 p.m. by: hsueh   email:
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last update: March 8, 2017, 3:01 p.m. by: hsueh    email:



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