Search results for "mTOR"
showing 10 items of 275 documents
GSK-3 as potential target for therapeutic intervention in cancer
2014
// James A. McCubrey 1 , Linda S. Steelman 1 , Fred E. Bertrand 2 , Nicole M. Davis 1 , Melissa Sokolosky 1 , Steve L. Abrams 1 , Giuseppe Montalto 3 , Antonino B. D’Assoro 4 , Massimo Libra 5 , Ferdinando Nicoletti 5 , Roberta Maestro 6 , Jorg Basecke 7,8 , Dariusz Rakus 9 , Agnieszka Gizak 9 Zoya Demidenko 10 , Lucio Cocco 11 , Alberto M. Martelli 11 and Melchiorre Cervello 12 1 Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC, USA 2 Department of Oncology, Brody School of Medicine at East Carolina University Greenville, NC, USA 3 Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy …
Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling
2019
Oncogenic HPV types are major human carcinogens. Under hypoxia, HPV-positive cancer cells can repress the viral E6/E7 oncogenes and induce a reversible growth arrest. This response could contribute to therapy resistance, immune evasion, and tumor recurrence upon reoxygenation. Here, we uncover evidence that HPV oncogene repression is mediated by hypoxia-induced activation of canonical PI3K/mTORC2/AKT signaling. AKT-dependent downregulation of E6/E7 is only observed under hypoxia and occurs, at least in part, at the transcriptional level. Quantitative proteome analyses identify additional factors as candidates to be involved in AKT-dependent E6/E7 repression and/or hypoxic PI3K/mTORC2/AKT ac…
Canonical correlation in multivariate time series analysis
1997
We analyze a class o f state space identification algorithms for time series, based on canonical correlation analysis in the ligth of recent results on stochastic systems theory calle d « subspace methods » .These can be describe as covariance estimation followed b y stochastic realization .The methods offer the major advantage o f converting the nonlinear parameter estimation phase in traditional V A R M A models identification in to the solution o f Riccati equation but introduce at the same time some no n trivial mathematical problem s related to positivity. The states o f the forward -backward innovations representation have an interpretation : Instrumental Variables estimators .
De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome
2014
Activating mutations in genes encoding phosphatidylinositol 3-kinase (PI3K)-AKT pathway components cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH, OMIM 603387)(1-3). Here we report that individuals with MPPH lacking upstream PI3K-AKT pathway mutations carry de novo mutations in CCND2 (encoding cyclin D2) that are clustered around a residue that can be phosphorylated by glycogen synthase kinase 313 (GSK-3 beta)(4). Mutant CCND2 was resistant to proteasomal degradation in vitro compared to wild-type CCND2. The PI3K-AKT pathway modulates GSK-3 beta activity(4), and cells from individuals with PIK3CA, PIK3R2 or AKT3 mutations showed similar CCND2 accumulation. CCND…
Hormonikorvaushoito ja luurankolihaksisto : estrogeenisten ja progestogeenisten komponenttien vaikutukset lihassoluviljelmässä
2010
Yksi merkittävimmistä ikääntymiseen liittyvistä tapahtumista on luurankolihasten heikentyminen. Sarkopenia eli lihaskato heikentää ennen kaikkea ikääntyvän ihmisen terveyttä ja sitä kautta elämänlaatua, mutta sen kustannukset myös sosiaali- ja terveydenhuollolle ovat suuret. Naisilla lihasten suorituskyky heikkenee merkittävästi vaihdevuosien aikana, jolloin myös estrogeenin ja progesteronin tasot laskevat. Etenkin 17β-estradiolin (E2) tuotanto munasarjoissa loppuu vaihdevuosien aikana. Estrogeenin tiedetään vaikuttavan primaaristen sukupuoliominaisuuksien lisäksi myös moniin muihin kudoksiin, kuten luuhun ja lihaksiin. Vaihdevuosien mukanaan tuomia oireita hoidetaan usein estradiolia ja pr…
Effects of combined hormone replacement therapy or its effective agents on the IGF-1 pathway in skeletal muscle.
2010
Objectives To investigate the effects of combined hormone replacement therapy (HRT) and its effective agents on the IGF-1 signaling pathway. Design and methods To examine the effects of HRT on skeletal muscle in vivo, we utilized pre- and post-intervention samples from a randomized double blinded trial with 50–57-year-old women. The intervention included the year-long use of either HRT preparation (2 mg 17β-estradiol, E2; 1 mg norethisterone acetate, NETA, n = 10) or placebo (CO, n = 9). Microarray technology and quantitative PCR (qPCR) were used to study the expression of insulin-like growth factor I (IGF-1) and its splice variants as well as IGF-1 receptor, Akt1, mTOR, FOXO1, FOXO3, atrog…
Hormone replacement therapy enhances IGF-1 signaling in skeletal muscle by diminishing miR-182 and miR-233 expressions: A study on postmenopausal mon…
2014
MiRNAs are fine-tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co-twin case–control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen-based hormone replacement therapy (HRT) to explore estrogen-dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54–62- years-old monozygotic female twin pairs discordant for HRT (median 7 years). MCF-7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen’s causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the ac…
Acetic Acid Mediated for One-Pot Synthesis of Novel Pyrazolyl s-Triazine Derivatives for the Targeted Therapy of Triple-Negative Breast Tumor Cells (…
2022
Here, we described the synthesis of novel pyrazole-s-triazine derivatives via an easy one-pot procedure for the reaction of β-dicarbonyl compounds (ethylacetoacetate, 5,5-dimethyl-1,3-cyclohexadione or 1,3-cyclohexadionone) with N,N-dimethylformamide dimethylacetal, followed by addition of 2-hydrazinyl-4,6-disubstituted-s-triazine either in ethanol-acetic acid or neat acetic acid to afford a novel pyrazole and pyrazole-fused cycloalkanone systems. The synthetic protocol proved to be efficient, with a shorter reaction time and high chemical yield with broad substrates. The new pyrazolyl-s-triazine derivatives were tested against the following cell lines: MCF-7 (breast cancer); MDA-MB-231 (tr…
Neural Stem Cells in the Adult Brain: From Benchside to Clinic
2012
Increasing evidence indicates that neural stem cells (NSCs) play an important role in sustaining cellular homeostasis and brain tissue restoration. The study of all mechanisms that control and modulate the function of NSC is a crucial step for the design of therapies against chronic neurodegenerative processes. In this special issue of the journal, we had the pleasure to edit the topic entitled “Neural Stem Cells in the Adult Brain: From Benchside to Clinic.” This special compilation of paper was aimed to provide a global forum for publications of original peer-reviewed manuscripts that reported original research findings in the field of adult neural stem cell, including short communication…
Mutant HRAS as novel target for MEK and mTOR inhibitors.
2015
HRAS is a frequently mutated oncogene in cancer. However, mutant HRAS as drug target has not been investigated so far. Here, we show that mutant HRAS hyperactivates the RAS and the mTOR pathway in various cancer cell lines including lung, bladder and esophageal cancer. HRAS mutation sensitized toward growth inhibition by the MEK inhibitors AZD6244, MEK162 and PD0325901. Further, we found that MEK inhibitors induce apoptosis in mutant HRAS cell lines but not in cell lines lacking RAS mutations. In addition, knockdown of HRAS by siRNA blocked cell growth in mutant HRAS cell lines. Inhibition of the PI3K pathway alone or in combination with MEK inhibitors did not alter signaling nor had an imp…