Gauged Nambu-Jona-Lasinio model with extra dimensions

We investigate phase structure of the D (> 4)-dimensional gauged Nambu-Jona-Lasinio (NJL) model with $\delta(=D-4)$ extra dimensions compactified on TeV scale, based on the improved ladder Schwinger-Dyson (SD) equation in the bulk. We assume that the bulk running gauge coupling in the SD equation for the SU(N_c) gauge theory with N_f massless flavors is given by the truncated Kaluza-Klein effective theory and hence has a nontrivial ultraviolet fixed point (UVFP). We find the critical line in the parameter space of two couplings, the gauge coupling and the four-fermion coupling, which is similar to that of the gauged NJL model with fixed (walking) gauge coupling in four dimensions. It is shown that in the presence of such walking gauge interactions the four-fermion interactions become ``nontrivial'' even in higher dimensions, similarly to the four-dimensional gauged NJL model. Such a nontriviality holds only in the restricted region of the critical line (``nontrivial window'') with the gauge coupling larger than a non-vanishing value (``marginal triviality (MT)'' point), in contrast to the four-dimensional case where such a nontriviality holds for all regions of the critical line except for the pure NJL point. In the nontrivial window the renormalized effective potential yields a nontrivial interaction which is conformal invariant. The exisitence of the nontrivial window implies ``cutoff insensitivity'' of the physics prediction in spite of the ultraviolet dominance of the dynamics. In the formal limit D -> 4, the nontrivial window coincides with the known condition of the nontriviality of the four-dimensional gauged NJL model, $9/(2N_c) < N_f - N_c < 9/2 N_c$.Comment: 34 pages, 6 figures, references added, to appear in Phys.Rev.D. The title is changed in PR

Isolation and fine mapping of Rps6: An intermediate host resistance gene in barley to wheat stripe rust

A plant may be considered a nonhost of a pathogen if all known genotypes of a plant species are resistant to all known isolates of a pathogen species. However, if a small number of genotypes are susceptible to some known isolates of a pathogen species this plant maybe considered an intermediate host. Barley (Hordeum vulgare) is an intermediate host for Puccinia striiformis f. sp. tritici (Pst), the causal agent of wheat stripe rust. We wanted to understand the genetic architecture underlying resistance to Pst and to determine whether any overlap exists with resistance to the host pathogen, Puccinia striiformis f. sp. hordei (Psh). We mapped Pst resistance to chromosome 7H and show that host and intermediate host resistance is genetically uncoupled. Therefore, we designate this resistance locus Rps6. We used phenotypic and genotypic selection on F2:3 families to isolate Rps6 and fine mapped the locus to a 0.1 cM region. Anchoring of the Rps6 locus to the barley physical map placed the region on two adjacent fingerprinted contigs. Efforts are now underway to sequence the minimal tiling path and to delimit the physical region harbouring Rps6. This will facilitate additional marker development and permit identification of candidate genes in the region

Triptolide (TPL) Inhibits Global Transcription by Inducing Proteasome-Dependent Degradation of RNA Polymerase II (Pol II)

Triptolide (TPL), a key biologically active component of the Chinese medicinal herb Tripterygium wilfordii Hook. f., has potent anti-inflammation and anti-cancer activities. Its anti-proliferative and pro-apoptotic effects have been reported to be related to the inhibition of Nuclear Factor κB (NF-κB) and Nuclear Factor of Activated T-cells (NFAT) mediated transcription and suppression of HSP70 expression. The direct targets and precise mechanisms that are responsible for the gene expression inhibition, however, remain unknown. Here, we report that TPL inhibits global gene transcription by inducing proteasome-dependent degradation of the largest subunit of RNA polymerase II (Rpb1) in cancer cells. In the presence of proteosome inhibitor MG132, TPL treatment causes hyperphosphorylation of Rpb1 by activation of upstream protein kinases such as Positive Transcription Elongation Factor b (P-TEFb) in a time and dose dependent manner. Also, we observe that short time incubation of TPL with cancer cells induces DNA damage. In conclusion, we propose a new mechanism of how TPL works in killing cancer. TPL inhibits global transcription in cancer cells by induction of phosphorylation and subsequent proteasome-dependent degradation of Rpb1 resulting in global gene transcription, which may explain the high potency of TPL in killing cancer

Resistance of MLL–AFF1-positive acute lymphoblastic leukemia to tumor necrosis factor-alpha is mediated by S100A6 upregulation

Mixed-lineage leukemia (MLL)–AFF1 (MLL–AF4)-positive acute lymphoblastic leukemia (ALL) is associated with poor prognosis, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The resistance to graft-versus-leukemia (GVL) effects may be responsible for the poor effect of allo-HSCT on MLL–AFF1-positive ALL. Cytotoxic effector mechanisms mediated by tumor necrosis factor-alpha (TNF-α) was reported to contribute to the GVL effect. We showed that MLL–AFF1-positive ALL cell lines are resistant to TNF-α. To examine the mechanism of resistance to TNF-α of MLL–AFF1-positive leukemia, we focused on S100A6 as a possible factor. Upregulation of S100A6 expression and inhibition of the p53–caspase 8–caspase 3 pathway were observed only in MLL–AFF1-positive ALL cell lines in the presence of TNF-α. The effect of S100A6 on resistance to TNF-α by inhibition of the p53–caspase 8–caspase 3 pathway of MLL–AFF1-positive ALL cell lines were also confirmed by analysis using small interfering RNA against S100A6. This pathway was also confirmed in previously established MLL–AFF1 transgenic mice. These results suggest that MLL–AFF1-positive ALL escapes from TNF-α-mediated apoptosis by upregulation of S100A6 expression, followed by interfering with p53–caspase 8–caspase 3 pathway. These results suggest that S100A6 may be a promising therapeutic target for MLL–AFF1-positive ALL in combination with allo-HSCT

Transcriptomal profiling of the cellular response to DNA damage mediated by Slug (Snai2)

Snai2-deficient cells are radiosensitive to DNA damage. The function of Snai2 in response to DNA damage seems to be critical for its function in normal development and cancer. Here, we applied a functional genomics approach that combined gene-expression profiling and computational molecular network analysis to obtain global dissection of the Snai2-dependent transcriptional response to DNA damage in primary mouse embryonic fibroblasts (MEFs), which undergo p53-dependent growth arrest in response to DNA damage. Although examination of the response showed that overall expression of p53 target gene expression patterns was similarly altered in both control and Snai2-deficient cells, we have identified and validated candidate Snai2 target genes linked to Snai2 gene function in response to DNA damage. This work defines for the first time the effect of Snai2 on p53 target genes in cells undergoing growth arrest, elucidates the Snai2-dependent molecular network induced by DNA damage, points to novel putative Snai2 targets, and suggest a mechanistic model, which has implications for cancer management

How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine

Carcinogenesis is an evolutionary process that establishes the ‘hallmarks of cancer' by natural selection of cell clones that have acquired advantageous heritable characteristics. Evolutionary adaptation has also been proposed as a mechanism that promotes drug resistance during systemic cancer therapy. This review summarises the evidence for the evolution of resistance to cytotoxic and targeted anti-cancer drugs according to Darwinian models and highlights the roles of genomic instability and high intra-tumour genetic heterogeneity as major accelerators of this evolutionary process. Clinical implications and strategies that may prevent the evolution of resistance or target the origins of genetic heterogeneity are discussed. New technologies to measure intra-tumour heterogeneity and translational research on serial biopsies of cancer lesions during and after therapeutic intervention are identified as key areas to further the understanding of determinants and mechanisms of the evolution of drug resistance

Slug expression is an independent prognostic parameter for poor survival in colorectal carcinoma patients

Slug, a member of the Snail family of transcription factors, plays a crucial role in the regulation of epithelial-mesenchymal transition (EMT) by suppressing several epithelial markers and adhesion molecules including E-cadherin. Recently, several studies have reported Slug to be expressed in breast carcinoma, oesophageal carcinoma accompanied with shorter survival. In this study, we first investigated expression of Slug mRNA in five colorectal carcinoma cell lines by reverse transcription–polymerase chain reaction. Furthermore, we investigated Slug and E-cadherin expression by immunohistochemistry in 138 patients with colorectal carcinoma. Slug mRNA was clearly expressed in four out of five colorectal carcinoma cell lines. Positive expression of Slug and E-cadherin was observed in 37 and 58% of cases, respectively. The positive expression of Slug was significantly associated with Dukes stage and distant metastasis (P=0.0027 and 0.0007), and the positive expression of Slug had a significant impact on patient overall survival (P<0.0001, log-rank test). Moreover, patients with positive expression of Slug and reduced expression of E-cadherin showed the worst prognosis (P<0.0001, log-rank test). Multivariate analysis indicated that Slug expression was an independent prognostic factor. These results suggest that positive Slug expression in colorectal carcinoma patients may become a significant parameter of poor prognosis

Hsc70 Focus Formation at the Periphery of HSV-1 Transcription Sites Requires ICP27

The cellular chaperone protein Hsc70, along with components of the 26S proteasome and ubiquitin-conjugated proteins have been shown to be sequestered in discrete foci in the nuclei of herpes simplex virus 1 (HSV-1) infected cells. We recently reported that cellular RNA polymerase II (RNAP II) undergoes proteasomal degradation during robust HSV-1 transcription, and that the immediate early protein ICP27 interacts with the C-terminal domain and is involved in the recruitment of RNAP II to viral transcription/replication compartments.Here we show that ICP27 also interacts with Hsc70, and is required for the formation of Hsc70 nuclear foci. During infection with ICP27 mutants that are unable to recruit RNAP II to viral replication sites, viral transcript levels were greatly reduced, viral replication compartments were poorly formed and Hsc70 focus formation was curtailed. Further, a dominant negative Hsc70 mutant that cannot hydrolyze ATP, interfered with RNAP II degradation during HSV-1 infection, and an increase in ubiquitinated forms of RNAP II was observed. There was also a decrease in virus yields, indicating that proteasomal degradation of stalled RNAP II complexes during robust HSV-1 transcription and replication benefits viral gene expression.We propose that one function of the Hsc70 nuclear foci may be to serve to facilitate the process of clearing stalled RNAP II complexes from viral genomes during times of highly active transcription

Integrin/Fak/Src-mediated regulation of cell survival and anoikis in human intestinal epithelial crypt cells: selective engagement and roles of PI3-K isoform complexes

In human intestinal epithelial crypt (HIEC) cells, the PI3-K/Akt-1 pathway is crucial for the promotion of cell survival and suppression of anoikis. Class I PI3-K consists of a complex formed by a catalytic (C) and regulatory (R) subunit. Three R (p85α, β, and p55γ) and four C (p110α, β, γ and δ) isoforms are known. Herein, we analyzed the expression of PI3-K isoforms in HIEC cells and determined their roles in cell survival, as well as in the β1 integrin/Fak/Src-mediated suppression of anoikis. We report that: (1) the predominant PI3-K complexes expressed by HIEC cells are p110α/p85β and p110α/p55γ; (2) the inhibition and/or siRNA-mediated expression silencing of p110α, but not that of p110β, γ or δ, results in Akt-1 down-activation and consequent apoptosis; (3) the expression silencing of p85β or p55γ, but not that of p85α, likewise induces Akt-1 down-activation and apoptosis; however, the impact of a loss of p55γ on both Akt-1 activation and cell survival is significantly greater than that from the loss of p85β; and (4) both the p110α/p85β and p110α/p55γ complexes are engaged by β1 integrin/Fak/Src signaling; however, the engagement of p110α/p85β is primarily Src-dependent, whereas that of p110α/p55γ is primarily Fak-dependent (but Src-independent). Hence, HIEC cells selectively express PI3-K isoform complexes, translating into distinct roles in Akt-1 activation and cell survival, as well as in a selective engagement by Fak and/or Src within the context of β1 integrin/Fak/Src-mediated suppression of anoikis