Differential Requirement for p21  Activation in the Metabolic Signaling by Insulin

Reusch, Jane E.B.; Bhuripanyo, Penpun; Carel, Kirstin; Leitner, J. Wayne; Hsieh, P.; Depaolo, D.; Draznin, Boris

doi:10.1074/jbc.270.5.2036

Cited by 35 publications

(24 citation statements)

References 25 publications

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“…Lovastatin, however, was added 24 h prior to insulin addition. It has previously been shown that shorter preincubation times with lovastatin had little to no effect on the insulin-stimulated MAP kinase activity (22,43). RNA Isolation and Northern Analysis-Total RNA was extracted using the guanidinium isothiocyanate method described by Chomczynski and Sacchi (45).…”

Section: Methodsmentioning

confidence: 99%

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Insulin Regulation of Glucose-6-phosphate Dehydrogenase Gene Expression Is Rapamycin-sensitive and Requires Phosphatidylinositol 3-Kinase

Wagle¹,

Jivraj²,

Garlock³

et al. 1998

Journal of Biological Chemistry

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Glucose-6-phosphate dehydrogenase (G6PDH) controls the flow of carbon through the pentose phosphate pathway and also produces NADPH needed for maintenance of reduced glutathione and reductive biosynthesis. Hepatic expression of G6PDH is known to respond to several dietary and hormonal factors, but the mechanism behind regulation of this expression has not been characterized. We show that insulin similarly induces expression of endogenous hepatic G6PDH and a reporter construct containing 935 base pairs of the G6PDH promoter linked to luciferase in transient transfection assays. Using well tested and structurally distinct inhibitors of Ras farnesylation, lovastatin and B581, and a specific inhibitor of mitogen-activated protein kinase kinase activation, PD 98059, we show that the Ras/Raf/ mitogen-activated protein kinase pathway is not utilized for the insulin-induced stimulation of G6PDH gene expression in primary rat hepatocytes. Similarly, using well characterized inhibitors of phosphatidylinositol 3-kinase, wortmannin and LY 294002, we show that PI 3-kinase activity is necessary for the induction of G6PDH expression by insulin. Rapamycin, an inhibitor of FRAP protein, which is involved in the activation of pp70 S6 kinase, blocks the insulin induction of G6PDH, suggesting that S6 kinase is also necessary for the insulin induction of G6PDH expression.

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Section: Methodsmentioning

confidence: 99%

“…Once activated by phosphorylation, the Shc proteins associate with various downstream effector molecules including Grb2 and the guanine nucleotide-releasing factor (21). Grb2/SOS interaction plays a role in the insulin activation of Ras, since SOS facilitates the exchange of GDP for GTP on Ras proteins (22).…”

mentioning

confidence: 99%

Insulin Regulation of Glucose-6-phosphate Dehydrogenase Gene Expression Is Rapamycin-sensitive and Requires Phosphatidylinositol 3-Kinase

Wagle¹,

Jivraj²,

Garlock³

et al. 1998

Journal of Biological Chemistry

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“…Activated FOXO1 induces Npy transcription and represses Pomc expression, while inhibitory phosphorylation of FOXO1 causes its translocation out of the nucleus, resulting in increased Pomc mRNA and decreased Npy mRNA levels (Kim et al 2006, Kitamura et al 2006, Plum et al 2006a. Insulin signal transduction also stimulates the MAPK pathway leading to mitogenesis (Reusch et al 1995).…”

Section: Introductionmentioning

confidence: 99%

Cellular insulin resistance disrupts hypothalamic mHypoA-POMC/GFP neuronal signaling pathways

Nazarians-Armavil¹,

Chalmers²,

Lee³

et al. 2013

Journal of Endocrinology

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POMC neurons play a central role in the maintenance of whole-body energy homeostasis. This balance requires proper regulation of POMC neurons by metabolic hormones, such as insulin. However, the heterogeneous cellular population of the intact hypothalamus presents challenges for examining the molecular mechanisms underlying the potent anorexigenic effects of POMC neurons, and there is currently a complete lack of mature POMC neuronal cell models for study. To this end, we have generated novel, immortalized, adult-derived POMC-expressing/a-MSH-secreting cell models, mHypoA-POMC/GFP lines 1-4, representing the fluorescence-activated cell-sorted POMC population from primary POMCeGFP mouse hypothalamus. The presence of Pomc mRNA in these cell lines was confirmed, and a-MSH was detected via immunofluorescence. a-MSH secretion in the mHypoA-POMC/GFP-1 was found to increase in response to 10 ng/ml ciliary neurotrophic factor (CNTF) or 10 nM insulin as determined by enzyme immunoassay. Further experiments using the mHypoA-POMC/GFP-1 cell line revealed that 10 ng/ml CNTF increases Pomc mRNA at 1 and 2 h after treatment, whereas insulin elicited an increase in Pomc mRNA level and decreases in insulin receptor (Insr (Ir)) mRNA level at 4 h. Furthermore, the activation of IR-mediated downstream second messengers was examined by western blot analysis, following the induction of cellular insulin resistance, which resulted in a loss of insulin-mediated regulation of Pomc and Ir mRNAs. The development of these immortalized neurons will be invaluable for the elucidation of the cellular and molecular mechanisms that underlie POMC neuronal function under normal and perturbed physiological conditions.

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“…This could suggest that the TSH stimulation of the mevalonate biosynthetic pathway could be required for the TSH-induced proliferation of these cells. To test this hypothesis, we have investigated the effect of lovastatin, an HMG-CoA reductase inhibitor (14,15), on protein or DNA synthesis induced by insulin or TSH.…”

Section: Introductionmentioning

confidence: 99%

Insulin and TSH promote growth in size of PC Cl3 rat thyroid cells, possibly via a pathway different from DNA synthesis: comparison with FRTL-5 cells

Kimura¹,

Dumont²,

Fusco

et al. 1999

European Journal of Endocrinology

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In the rat thyroid cell lines PC Cl3, FRTL-5 and WRT, proliferation is mainly regulated by insulin or IGF, and TSH. However, the mechanism regulating cell mass doubling prior to division is still unknown. Our laboratory has shown that in dog thyroid cells insulin promotes growth in size while TSH in the presence of insulin triggers DNA replication. In the absence of insulin, TSH has no effect on cell growth. In this report we investigated insulin action on both cell mass and DNA synthesis and its modulation by TSH and insulin in PC Cl3 and FRTL-5 cells. In PC Cl3 cells, insulin activated not only DNA synthesis but also protein synthesis and accumulation. Although TSH potentiated the stimulation of DNA synthesis induced by insulin, enhancement of protein synthesis by both agents was additive. All TSH effects were reproduced by forskolin. Similar effects were also obtained in FRTL-5 cells. This suggests that insulin and TSH, via cAMP, modulate both growth in size and DNA replication in these cell lines.Lovastatin, which blocks 3-hydroxy-3-methylglutaryl coenzyme A reductase, decreased the induction of DNA synthesis, but not of protein synthesis induced by insulin or TSH in PC Cl3 cells. In FRTL-5 cells, lovastatin reduced protein and DNA synthesis stimulated by insulin but not TSH-induced protein synthesis. Taking these data together, we propose that insulin and/or TSH both modulate cell mass doubling and DNA synthesis in these cell lines, presumably via different pathways, and that there are at least two pathways which regulate growth in size in FRTL-5 thyroid cells: one triggered by insulin, which is lovastatin sensitive, and the other activated by TSH, which is not sensitive to lovastatin.

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Differential Requirement for p21 Activation in the Metabolic Signaling by Insulin

Cited by 35 publications

References 25 publications

Insulin Regulation of Glucose-6-phosphate Dehydrogenase Gene Expression Is Rapamycin-sensitive and Requires Phosphatidylinositol 3-Kinase

Insulin Regulation of Glucose-6-phosphate Dehydrogenase Gene Expression Is Rapamycin-sensitive and Requires Phosphatidylinositol 3-Kinase

Cellular insulin resistance disrupts hypothalamic mHypoA-POMC/GFP neuronal signaling pathways

Insulin and TSH promote growth in size of PC Cl3 rat thyroid cells, possibly via a pathway different from DNA synthesis: comparison with FRTL-5 cells

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