Growth factor – regulated expression of enzymes involved in nucleotide biosynthesis: a novel mechanism of growth factor action

Gassmann, Marcus; Stanzel, Andreas; Werner, Sabine

doi:10.1038/sj.onc.1203120

Cited by 23 publications

(24 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First, the intracellular ATP concentration is decreased in mouse embryo fibroblasts that lack Akt1 and Akt2 (8). Second, treating keratinocytes with epidermal or keratinocyte growth factor, both of which activate PI3K and Akt, increases expression of several purine synthetic enzymes (9). Third, the intracellular ATP concentration is 3 times higher in Rat1a fibroblasts that overexpress myristoylated, constitutively active Akt compared with control cells (8,10).…”

Section: Reaction 6)mentioning

confidence: 94%

“…Briefly about 10 ϫ 10 6 C2C12 cells were extracted rapidly in ice-cold 0.4 N perchloric acid, precipitated macromolecules were removed by centrifugation, and the lysates were neutralized with KHCO 3 . Purine nucleotides in the samples were analyzed by HPLC on a strong anion exchange column using the same system as described for following [6][7][8][9][10][11][12][13][14] C]glucose incorporation into ATP.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The Phosphatidylinositol 3-Kinase/Akt Cassette Regulates Purine Nucleotide Synthesis

Wang

Fridman

Blackledge

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is highly conserved throughout evolution and regulates cell size and survival and cell cycle progression. It regulates the latter by stimulating procession through G 1 and the G 1 /S phase transition. Entry into S phase requires an abundant supply of purine nucleotides, but the effect of the PI3K/Akt pathway on purine synthesis has not been studied. We now show that the PI3K/Akt cassette regulates both de novo and salvage purine nucleotide synthesis in insulin-responsive mouse mesenchymal cells. We found that serum and insulin stimulated de novo purine synthesis in serum-starved cells largely through PI3K/Akt signaling, and pharmacologic and genetic inhibition of PI3K/Akt reduced de novo synthesis by 75% in logarithmically growing cells. PI3K/ Akt regulated early steps of de novo synthesis by modulating phosphoribosylpyrophosphate production by the non-oxidative pentose phosphate pathway and late steps by modulating activity of the bifunctional enzyme aminoimidazole-carboxamide ribonucleotide transformylase IMP cyclohydrolase, an enzyme not previously known to be regulated. The effects of PI3K/Akt on purine nucleotide salvage were likely through regulating phosphoribosylpyrophosphate availability. These studies define a new mechanism whereby the PI3K/Akt cassette functions as a master regulator of cellular metabolism and a key player in oncogenesis.Insulin and a variety of other growth factors activate the PI3K 3 /Akt (protein kinase B) pathway. Activated Akt regulates several intracellular processes including protein synthesis, glucose metabolism, and cell cycle progression (1, 2). Frequently regulation occurs at more than one step. (i) Akt increases protein synthesis by activating mTOR, which regulates the activities of S6 kinase-1 and 4E-BP1, two translational regulators (3).(ii) Akt regulates glucose metabolism by inducing translocation of glucose transporters to the cell surface, by activating hexokinase, and by inhibiting glycogen synthase kinase-3 (4). (iii) Akt stimulates the cell cycle by phosphorylating, and thereby inhibiting, the cyclin-dependent kinase inhibitors p21 Cip/WAF1 and p27Kip1 and the FOXO transcription factors and through phosphorylation of glycogen synthase kinase-3, which regulates the G 1 cyclins, cyclins D and E (2, 5).The de novo synthesis of purines consists of 10 sequential steps, starting with phosphoribosylpyrophosphate (PRPP) and ending with IMP; the latter is converted to AMP or GMP (see Fig. 1). PRPP amidotransferase catalyzes the first committed step of the pathway (see Fig. 1, reaction 2) and is subject to feedback inhibition by purine nucleotides; therefore, it has been considered a major point of pathway regulation (6). We showed previously that production of ribose 5-phosphate, the immediate precursor of PRPP and an end product of the pentose phosphate pathway, also contributes to the regulation of purine synthesis (7). Salvage purine nucleotide synthesis involves hypoxanthine phosphoribosyltransferase, which...

show abstract

Section: Reaction 6)mentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

The Phosphatidylinositol 3-Kinase/Akt Cassette Regulates Purine Nucleotide Synthesis

Wang

Fridman

Blackledge

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…It is very likely related to its function in adenine nucleotide biosynthesis [21][22][23][24]. Adenine nucleotide biosynthesis increases several folds in the hypertrophied rodent heart and this enhancement of adenine nucleotide synthesis occurs very early and precedes the increase of protein synthesis [7,8,[21][22][23][24][25].…”

Section: Discussionmentioning

confidence: 99%

The adenylosuccinate synthetase‐1 gene is activated in the hypertrophied heart

Wen¹,

Xia²,

Young³

et al. 2002

J Cellular Molecular Medi

View full text Add to dashboard Cite

Cardiac hypertrophy is an adaptive response of the heart to stress, including hypertension, mechanical overload, myocardial infarction and genetic mutations in cardiac contractile protein genes [1,2]. In response to stress, intracellular Ca 2+ concentrations increase [3][4][5][6], consistent with a role for Ca 2+ in coordinating physiologic responses with enhanced cardiac output, both acutely and chronically. Thus Ca 2+ provides an important signal for the development of cardiac hypertrophy. Although changes in the expression of contractile and structural genes are well known in cardiac hypertrophy, the genes encoding enzymes of cardiac metabolism and their signal pathways in the cardiac hypertrophy are less well studied. In the current study we were especially interested in changes in cardiomyocyte nucleotide metabolism in response to cardiac hypertrophy, and have focused on the muscle specific isoform of adenylosuccinate synthetase 1 AbstractAdenylosuccinate synthetase 1 (ADSS1) functions as an important component in adenine nucleotide biosynthesis and is abundant in the heart. Here we report that the Adss1 gene is up-regulated in two in vivo rodent models of surgically induced cardiac hypertrophy. In addition, we examined an in vitro hypertrophy system of rat neonatal cardiomyocytes treated with angiotensin II to study Adss1 gene regulation. We show that this stimulus triggers a signaling cascade that results in the activation of the Adss1 gene. The induction of Adss1 gene expression was blocked by cyclosporin A in vitro, suggesting that calcineurin, a calmodulin activated phosphatase, is involved in this signaling pathway. Consistent with this view we provide evidence that the induction of Adss1 by angiotension II requires the presence of an NFAT binding site located 556 base pairs upstream of the Adss1 transcription start site. We propose that ADSS1 plays a role in the development of cardiac hypertrophy through its function in adenine nucleotide biosynthesis.

show abstract

“…This might explain the upregulation of adenylosuccinate synthetase (ADSS), an enzyme essential in ATP production. Accordingly, this enzyme was reported to be upregulated in the healing edges of epithelial wounds [26]. …”

Section: Resultsmentioning

confidence: 99%

In GERD patients, mucosal repair associated genes are upregulated in non‐inflamed oesophageal epithelium

Vries

Linde

Herwaarden

et al. 2009

J Cellular Molecular Medi

View full text Add to dashboard Cite

Previous studies addressing the effects of acid reflux and PPI therapy on gene expression in oesophageal epithelium concentrated on inflamed tissue. We aimed to determine changes in gene expression in non-inflamed oesophageal epithelium of GERD patients. Therefore, we included 20 GERD patients with pathological total 24-hr acid exposure of 6–12% and SAP ≥ 95%. Ten patients discontinued PPI treatment (PPI-), 10 took pantoprazole 40 mg bid (PPI+). Ten age/sex-matched healthy controls were recruited. Biopsies were taken from non-inflamed mucosa 6 cm and 16 cm proximal to the squamocolumnar junction (SCJ). Gene expression profiling of biopsies from 6 cm was performed on Human Genome U133 Plus 2.0 arrays (Affymetrix). Genes exhibiting a fold change >1.4 (t-test P-value < 1E– 4) were considered differentially expressed. Results were confirmed by real-time RT-PCR. In PPI- patients, 92 microarray probesets were deregulated. The majority of the corresponding genes were associated with cell–cell contacts, cytoskeletal reorganization and cellular motility, suggesting facilitation of a migratory phenotype. Genes encoding proteins with anti-apoptotic or anti-proliferative functions or stress-protective functions were also deregulated. No probesets were deregulated in PPI+ patients. QPCR analysis of 20 selected genes confirmed most of the deregulations in PPI- patients, and showed several deregulated genes in PPI+ patients as well. In the biopsies taken at 16 cm QPCR revealed no deregulations of the selected genes. We conclude that upon acid exposure, oesophageal epithelial cells activate a process globally known as epithelial restitution: up-regulation of anti-apoptotic, anti-oxidant and migration associated genes. Possibly this process helps maintaining barrier function.

show abstract

Growth factor – regulated expression of enzymes involved in nucleotide biosynthesis: a novel mechanism of growth factor action

Cited by 23 publications

References 44 publications

The Phosphatidylinositol 3-Kinase/Akt Cassette Regulates Purine Nucleotide Synthesis

The Phosphatidylinositol 3-Kinase/Akt Cassette Regulates Purine Nucleotide Synthesis

The adenylosuccinate synthetase‐1 gene is activated in the hypertrophied heart

In GERD patients, mucosal repair associated genes are upregulated in non‐inflamed oesophageal epithelium

Contact Info

Product

Resources

About