AKT2 (v-akt murine thymoma viral oncogene homolog 2)

Review on AKT2 (v-akt murine thymoma viral oncogene homolog 2), with data on DNA, on the protein encoded, and where the gene is implicated

Phosphorylation of the androgen receptor is associated with reduced survival in hormonerefractory prostate cancer patients

Cell line studies demonstrate that the PI3K/Akt pathway is upregulated in hormone-refractory prostate cancer (HRPC) and can result in phosphorylation of the androgen receptor (AR). The current study therefore aims to establish if this has relevance to the development of clinical HRPC. Immunohistochemistry was employed to investigate the expression and phosphorylation status of Akt and AR in matched hormone-sensitive and -refractory prostate cancer tumours from 68 patients. In the hormone-refractory tissue, only phosphorylated AR (pAR) was associated with shorter time to death from relapse (<i>P</i>=0.003). However, when an increase in expression in the transition from hormone-sensitive to -refractory prostate cancer was investigated, an increase in expression of PI3K was associated with decreased time to biochemical relapse (<i>P</i>=0.014), and an increase in expression of pAkt<sup>473</sup> and pAR<sup>210</sup> were associated with decreased disease-specific survival (<i>P</i>=0.0019 and 0.0015, respectively). Protein expression of pAkt<sup>473</sup> and pAR<sup>210</sup> also strongly correlated (<i>P</i><0.001, c.c.=0.711) in the hormone-refractory prostate tumours. These results provide evidence using clinical specimens, that upregulation of the PI3K/Akt pathway is associated with phosphorylation of the AR during development of HRPC, suggesting that this pathway could be a potential therapeutic target

3-O-Benzhydryl-2,5-dide­oxy-2,5-imino-2-C-methyl-l-lyxono-1,4-lactone

The title bicyclic lactone, C19H19NO3, is an inter­mediate in the synthesis of chiral α-methyl­prolines and branched C-methyl pyrrolidines; the absolute configuration was determined by the use of d-erythronolactone as the starting material. It exhibits no unusual crystal packing features, and each mol­ecule acts as a donor and acceptor for one C—H⋯O hydrogen bond

1-Methyl-1-azonia-3,5-diaza-7-phosphatricyclo­[3.3.1.13,7]decane tetra­fluoro­borate

The title compound, C7H15N3P+·BF4 − or [PTA-Me][BF4], is the N-methyl­ated derivative of the well known water-soluble amino­phosphine 1,3,5-triaza-7-phosphaadamantane (PTA). The asymmetric unit consists of a cage-like cation [PTA-Me]+ and a disordered tetra­fluoro­borate anion; two F atoms are disordered equally over two sites. A network of weak inter­molecular C—H⋯F hydrogen bonds results in a three-dimensional supra­molecular assembly

5-Chloro­benzothia­zole-2-spiro-3′-indolin-2′-one

The title compound, C14H9ClN2OS, crystallizes with two unique mol­ecules, A and B, in the asymmetric unit. The five-membered rings of the benzothia­zole groups in both mol­ecules adopt an envelope conformation [puckering parameters: q 2 = 0.242 (1) Å and ϕ2 = 217.5 (4)° for A, and q 2 = 0.234 (1) Å and ϕ2 = 37.7 (4)° for B]. The five-membered rings of the indolinone groups in both mol­ecules are also not planar, with a twisted conformation [puckering parameters are q 2 = 0.112 (2) Å and ϕ2 = 126.3 (8)° for A, and q 2 = 0.108 (2) Å and ϕ2 = 306.4 (9)° for B]. In the crystal structure, there are inter­molecular N—H⋯O, N—H⋯S and C—H⋯O hydrogen-bonding inter­actions, forming the layers propagating normal to c

Three-dimensional hydrogen-bonded supra­molecular assembly in tetrakis­(1,3,5-triaza-7-phosphaadamantane)copper(I) chloride hexa­hydrate

The structure of the title compound, [Cu(PTA)4]Cl·6H2O (PTA is 1,3,5-triaza-7-phosphaadamantane, C6H12N3P), is composed of discrete monomeric [Cu(PTA)4]+ cations, chloride anions and uncoordinated water mol­ecules. The CuI atom exhibits tetra­hedral coordination geometry, involving four symmetry-equivalent P–bound PTA ligands. The structure is extended to a regular three-dimensional supra­molecular framework via numerous equivalent O—H⋯N hydrogen bonds between all solvent water mol­ecules (six per cation) and all PTA N atoms, thus simultaneously bridging each [Cu(PTA)4]+ cation with 12 neighbouring units in multiple directions. The study also shows that PTA can be a convenient ligand in crystal engineering for the construction of supra­molecular architectures

JNK3 Maintains Expression of the Insulin Receptor Substrate 2 (IRS2) in Insulin-Secreting Cells: Functional Consequences for Insulin Signaling

We have recently shown that silencing of the brain/islet specific c-Jun N-terminal Kinase3 (JNK3) isoform enhances both basal and cytokine-induced beta-cell apoptosis, whereas silencing of JNK1 or JNK2 has opposite effects. While it is known that JNK1 or JNK2 may promote apoptosis by inhibiting the activity of the pro-survival Akt pathway, the effect of JNK3 on Akt has not been documented. This study aims to determine the involvement of individual JNKs and specifically JNK3 in the regulation of the Akt signaling pathway in insulin-secreting cells. JNK3 silencing strongly decreases Insulin Receptor Substrate 2 (IRS2) protein expression, and blocks Akt2 but not Akt1 activation by insulin, while the silencing of JNK1 or JNK2 activates both Akt1 and Akt2. Concomitantly, the silencing of JNK1 or JNK2, but not of JNK3, potently phosphorylates the glycogen synthase kinase3 (GSK3β). JNK3 silencing also decreases the activity of the transcription factor Forkhead BoxO3A (FoxO3A) that is known to control IRS2 expression, in addition to increasing c-Jun levels that are known to inhibit insulin gene expression. In conclusion, we propose that JNK1/2 on one hand and JNK3 on the other hand, have opposite effects on insulin-signaling in insulin-secreting cells; JNK3 protects beta-cells from apoptosis and dysfunction mainly through maintenance of a normal IRS2 to Akt2 signaling pathway. It seems that JNK3 mediates its effects mainly at the transcriptional level, while JNK1 or JNK2 appear to mediate their pro-apoptotic effect in the cytoplasm

Evaluation of the dual mTOR / PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft models

We are grateful to Wyeth/Pfizer (ONC-EU-150) and to the Scottish Funding Council (SRDG HR07005) for support of this study.This study investigated the antitumour effects of two dual mTOR/PI3K inhibitors, gedatolisib (WYE-129587/PKI-587/PF-05212384) and PF-04691502 against a panel of six human patient derived ovarian cancer xenograft models. Both dual mTOR/PI3K inhibitors demonstrated antitumour activity against all xenografts tested. The compounds produced tumour stasis during the treatment period and upon cessation of treatment, tumours re-grew. In several models, there was an initial rapid reduction of tumour volume over the first week of treatment before tumour stasis. No toxicity was observed during treatment. Biomarker studies were conducted in two xenograft models; phospho-S6 (Ser235/236) expression (as a readout of mTOR activity) was reduced over the treatment period in the responding xenograft but expression increased to control (no treatment) levels on cessation of treatment. Phospho-AKT (Ser473) expression (as a readout of PI3K) was inhibited by both drugs but less markedly so than phospho-S6 expression. Initial tumour volume reduction on treatment and regrowth rate after treatment cessation was associated with phospho-S6/total S6 expression ratio. Both drugs produced apoptosis but minimally influenced markers of proliferation (Ki67, phospho-histone H3). These results indicate that mTOR/PI3K inhibition can produce broad spectrum tumour growth stasis in ovarian cancer xenograft models during continuous chronic treatment and this is associated with apoptosis.Publisher PDFPeer reviewe

Deregulated MicroRNAs in Myotonic Dystrophy Type 2

Myotonic Dystrophy Type-2 (DM2) is an autosomal dominant disease caused by the expansion of a CCTG tetraplet repeat. It is a multisystemic disorder, affecting skeletal muscles, the heart, the eye, the central nervous system and the endocrine system. Since microRNA (miRNA) expression is disrupted in Myotonic Dystrophy Type-1 and many other myopathies, miRNAs deregulation was studied in skeletal muscle biopsies of 13 DM2 patients and 13 controls. Eleven miRNAs were deregulated: 9 displayed higher levels compared to controls (miR-34a-5p, miR-34b-3p, miR-34c-5p, miR-146b-5p, miR-208a, miR-221-3p and miR-381), while 4 were decreased (miR-125b-5p, miR-193a-3p, miR-193b-3p and miR-378a-3p). To explore the relevance of DM2 miRNA deregulation, the predicted interactions between miRNA and mRNA were investigated. Global gene expression was analyzed in DM2 and controls and bioinformatic analysis identified more than 1,000 miRNA/mRNA interactions. Pathway and function analysis highlighted the involvement of the miRNA-deregulated mRNAs in multiple aspects of DM2 pathophysiology. In conclusion, the observed miRNA dysregulations may contribute to DM2 pathogenetic mechanisms