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"Roth, Richard A."
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Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2
Akt1 is frequently up-regulated in human tumors and has been shown to accelerate cell proliferation and to suppress programmed cell death; consequently, inhibition of the activity of Akt1 has been seen as an attractive target for therapeutic intervention. Paradoxically, hyperactivation of the Akt1 oncogene can also prevent the invasive behavior that underlies progression to metastasis. Here we show that overexpression of activated myr-Akt1 in human breast cancer cells phosphorylates and thereby targets the tumor suppressor tuberous sclerosis complex 2 (TSC2) for degradation, leading to reduced Rho-GTPase activity, decreased actin stress fibers and focal adhesions, and reduced motility and invasion. Overexpression of TSC2 rescues the migration phenotype of myr-Akt1-expressing tumor cells, and high levels of TSC2 in breast cancer patients correlate with increased metastasis and reduced survival. These data indicate that the functional properties of genes designated as oncogenes or tumor suppressor genes depend on the context of the cell type and the tissues studied, and suggest the need for caution in designing therapies targeting the function of individual genes in epithelial tissues. metastasis oncogene tumor suppressor
Journal Article
Inorganic Polyphosphate Stimulates Mammalian TOR, a Kinase Involved in the Proliferation of Mammary Cancer Cells
Inorganic polyphosphate (poly P), chains of hundreds of phosphate residues linked by \"high-energy\" bonds as in ATP, has been conserved from prebiotic times in all cells. Poly P is essential for a wide variety of functions in bacteria, including virulence in pathogens. In this study, we observe the unique and many-fold stimulation by poly P in vitro of the protein kinase mTOR (mammalian target of rapamycin). To explore the role of poly P in mammalian cells, a yeast polyphosphatase, PPX1, was inserted into the chromosomes of MCF-7 mammary cancer cells. The transfected cells are markedly deficient in their response to mitogens, such as insulin and amino acids, as seen in their failure to activate mTOR to phosphorylate one of its substrates, PHAS-I (the initiation factor 4E-binding protein). In addition, the transfected cells are severely reduced in their growth in a serum-free medium. On the basis of these findings, we suggest that poly P (and/or PPX1) serves as a regulatory factor in the activation of mTOR in the proliferative signaling pathways of animal cells.
Journal Article
Protein kinase B/Akt phosphorylation of PDE3A and its role in mammalian oocyte maturation
cGMP‐inhibited cAMP phosphodiesterase 3A (PDE3A) is expressed in mouse oocytes, and its function is indispensable for meiotic maturation as demonstrated by genetic ablation. Moreover, PDE3 activity is required for insulin/insulin‐like growth factor‐1 stimulation of
Xenopus
oocyte meiotic resumption. Here, we investigated the cAMP‐dependent protein kinase B (PKB)/Akt regulation of PDE3A and its impact on oocyte maturation. Cell‐free incubation of recombinant mouse PDE3A with PKB/Akt or cAMP‐dependent protein kinase A catalytic subunits leads to phosphorylation of the PDE3A protein. Coexpression of PDE3A with constitutively activated PKB/Akt (Myr‐Akt) increases PDE activity as well as its phosphorylation state. Injection of
pde3a
mRNA potentiates insulin‐dependent maturation of
Xenopus
oocytes and rescues the phenotype of
pde3
−/−
mouse oocytes. This effect is greatly decreased by mutation of any of the PDE3A serines 290–292 to alanine in both
Xenopus
and mouse. Microinjection of myr‐Akt in mouse oocytes causes
in vitro
meiotic maturation and this effect requires PDE3A. Collectively, these data indicate that activation of PDE3A by PKB/Akt‐mediated phosphorylation plays a role in the control of PDE3A activity in mammalian oocytes.
Journal Article
Insulin-Stimulated Akt Kinase Activity Is Reduced in Skeletal Muscle From NIDDM Subjects
The serine/threonine kinase Akt (PKB/Rac) has been implicated as playing a role in the insulin-signaling pathway to glucose transport. Little is known regarding the regulation of Akt kinase activity in insulin-sensitive tissues, such as skeletal muscle, or whether this regulation is altered in insulin-resistant states such as NIDDM. We examined the effect of insulin on Akt kinase activity in skeletal muscle from six NIDDM patients and six healthy subjects. Whole-body insulin sensitivity, assessed by the euglycemic-hyperinsulinemic clamp, was significantly lower in NIDDM subjects (P < 0.001), and this was accompanied by impaired in vitro insulin-stimulated glucose transport in skeletal muscle. In both groups, insulin induced a significant increase in Akt kinase activity, but the response to maximal insulin (60 nmol/1) was markedly reduced in skeletal muscle from NIDDM subjects (66% of control levels, P < 0.01). Impaired Akt kinase activity was not accompanied by decreased protein expression of Akt. Instead, a trend toward increased Akt expression was noted in skeletal muscle from NIDDM subjects (P < 0.1). These parallel defects in insulin-stimulated Akt kinase activity and glucose transport in diabetic skeletal muscle suggest that reduced Akt kinase activity may play a role in the development of insulin resistance in NIDDM.
Journal Article
A comparative study of the efficacy of intervention strategies on student electricity use in campus residence halls
Purpose
The purpose of this study was to determine whether, and how, electricity consumption by students in university residence halls were impacted through three intervention strategies.
Design/methodology/approach
The current investigation uses a quasi-experimental design by exposing freshman students in four matched residence halls and the use of three different interventions designed to encourage energy conservation, specifically electricity conservation. A control residence hall received no intervention. One residence hall had an energy dashboard prominently displayed. Another received various communications and programming designed to raise awareness of the need for energy conservation. A fourth residence hall had an energy dashboard and received programming. Electricity consumption among the residence halls was compared using multivariate analysis.
Findings
Students in all residence halls receiving interventions demonstrated significantly lower electricity consumption compared to the control residence hall. Across two years with different student populations, results were consistent: the residence hall receiving only the communications and programming, but not the dashboard, had the lowest electricity use. The residence hall with only the dashboard also demonstrated a significant but smaller decline in electricity use. Curiously, the residence hall wherein both interventions were used demonstrated the smallest decline in electricity use.
Practical implications
While total costs for the communications and programming are difficult to accurately assess, the results suggest that this approach is cost-effective when compared to the avoided cost of electricity and is superior in terms of electricity cost savings to both the dashboards and to the combined intervention. Results also suggest that any intervention is likely to induce a large enough electricity reduction to be cost-effective and there may be non-economic benefits as well.
Originality/value
This study takes advantage of the availability of four “matched” residence halls to approximate the rigor of a controlled quasi-experimental design to compare different strategies for inducing electricity consumption among freshman residents.
Journal Article
Improved Glucose Tolerance Restores Insulin-Stimulated Akt Kinase Activity and Glucose Transport in Skeletal Muscle From Diabetic Goto-Kakizaki Rats
The serine/threonine kinase Akt (protein kinase B [PKB] or related to A and C protein kinase [RAC] has recently been implicated to play a role in the signaling pathway to glucose transport. However, little is known concerning the regulation of Akt activity in insulinsensitive tissues such as skeletal muscle. To explore the role of hyperglycemia on Akt kinase activity in skeletal muscle, normal Wistar rats or Goto-Kakizaki (GK) diabetic rats were treated with phlorizin. Phlorizin treatment normalized fasting blood glucose and significantly improved glucose tolerance (P < 0.001) in GK rats, whereas in Wistar rats, the compound had no effect on glucose homeostasis. In soleus muscle from GK rats, maximal insulin-stimulated (120 nmol/l) Akt kinase activity was reduced by 68% (P < 0.01) and glucose transport was decreased by 39% (P < 0.05), compared with Wistar rats. Importantly, the defects at the level of Akt kinase and glucose transport were completely restored by phlorizin treatment. There was no significant difference in Akt kinase protein expression among the three groups. At a submaximal insulin concentration (2.4 nmol/l), activity of Akt kinase and glucose transport were unaltered. In conclusion, improved glucose tolerance in diabetic GK rats by phlorizin treatment fully restored insulin-stimulated activity of Akt kinase and glucose transport. Thus, hyperglycemia may directly contribute to the development of muscle insulin resistance through alterations in insulin action on Akt kinase and glucose transport.
Journal Article
Evidence of Insulin-Stimulated Phosphorylation and Activation of the Mammalian Target of Rapamycin Mediated by a Protein Kinase B Signaling Pathway
The effects of insulin on the mammalian target of rapamycin, mTOR, were investigated in 3T3-L1 adipocytes. mTOR protein kinase activity was measured in immune complex assays with recombinant PHAS-I as substrate. Insulin-stimulated kinase activity was clearly observed when immunoprecipitations were conducted with the mTOR antibody, mTAb2. Insulin also increased by severalfold the32P content of mTOR that was determined after purifying the protein from32P-labeled adipocytes with rapamycin· FKBP12 agarose beads. Insulin affected neither the amount of mTOR immunoprecipitated nor the amount of mTOR detected by immunoblotting with mTAb2. However, the hormone markedly decreased the reactivity of mTOR with mTAb1, an antibody that activates the mTOR protein kinase. The effects of insulin on increasing mTOR protein kinase activity and on decreasing mTAb1 reactivity were abolished by incubating mTOR with protein phosphatase 1. Interestingly, the epitope for mTAb1 is located near the COOH terminus of mTOR in a 20-amino acid region that includes consensus sites for phosphorylation by protein kinase B (PKB). Experiments were performed in MER-Akt cells to investigate the role of PKB in controlling mTOR. These cells express a PKB-mutant estrogen receptor fusion protein that is activated when the cells are exposed to 4-hydroxytamoxifen. Activating PKB with 4-hydroxytamoxifen mimicked insulin by decreasing mTOR reactivity with mTAb1 and by increasing the PHAS-I kinase activity of mTOR. Our findings support the conclusion that insulin activates mTOR by promoting phosphorylation of the protein via a signaling pathway that contains PKB.
Journal Article
Structure of the Receptor for Insulin-Like Growth Factor II: The Puzzle Amplified
The insulin-like growth factor II (IGF-II) is a polypeptide hormone with structural homologies to insulin and insulin-like growth factor I (IGF-I). In contrast to these other hormones, the in vivo function of IGF-II is not known. Although IGF-II can stimulate a broad range of biological responses in isolated cells, these responses have usually been found to be mediated by the insulin and IGF-I receptors. Recently, the receptor for IGF-II was found to also be the receptor for mannose-6-phosphate. Since this latter receptor has been implicated in targeting of lysosomal enzymes, the question is now raised of whether the same protein can also mediate metabolic responses to IGF-II.
Journal Article
Muscle fiber type-specific defects in insulin signal transduction to glucose transport in diabetic GK rats
Muscle fiber type-specific defects in insulin signal transduction to glucose transport in diabetic GK rats.
X M Song ,
Y Kawano ,
A Krook ,
J W Ryder ,
S Efendic ,
R A Roth ,
H Wallberg-Henriksson and
J R Zierath
Department of Clinical Physiology, Karolinska Hospital, Stockholm, Sweden.
Abstract
To determine whether defects in the insulin signal transduction pathway to glucose transport occur in a muscle fiber type-specific
manner, post-receptor insulin-signaling events were assessed in oxidative (soleus) and glycolytic (extensor digitorum longus
[EDL]) skeletal muscle from Wistar or diabetic GK rats. In soleus muscle from GK rats, maximal insulin-stimulated (120 nmol/l)
glucose transport was significantly decreased, compared with that of Wistar rats. In EDL muscle from GK rats, maximal insulin-stimulated
glucose transport was normal, while the submaximal response was reduced compared with that of Wistar rats. We next treated
diabetic GK rats with phlorizin for 4 weeks to determine whether restoration of glycemia would lead to improved insulin signal
transduction. Phlorizin treatment of GK rats resulted in full restoration of insulin-stimulated glucose transport in soleus
and EDL muscle. In soleus muscle from GK rats, submaximal and maximal insulin-stimulated insulin receptor substrate (IRS)-1
tyrosine phosphorylation and IRS-1-associated phosphatidylinositol (PI) 3-kinase activity were markedly reduced, compared
with that of Wistar rats, but only submaximal insulin-stimulated PI 3-kinase was restored after phlorizin treatment. In EDL
muscle, insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1-associated PI-3 kinase were not altered between GK and
Wistar rats. Maximal insulin-stimulated Akt (protein kinase B) kinase activity is decreased in soleus muscle from GK rats
and restored upon normalization of glycemia (Krook et al., Diabetes 46:2100-2114, 1997). Here, we show that in EDL muscle
from GK rats, maximal insulin-stimulated Akt kinase activity is also impaired and restored to Wistar rat levels after phlorizin
treatment. In conclusion, functional defects in IRS-1 and PI 3-kinase in skeletal muscle from diabetic GK rats are fiber-type-specific,
with alterations observed in oxidative, but not glycolytic, muscle. Furthermore, regardless of muscle fiber type, downstream
steps to PI 3-kinase (i.e., Akt and glucose transport) are sensitive to changes in the level of glycemia.
Journal Article