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Jun N-terminal kinases or JNKs play a critical role in death receptor-initiated extrinsic as well as mitochondrial intrinsic apoptotic pathways. JNKs activate apoptotic signaling by the upregulation of pro-apoptotic genes through the transactivation of specific transcription factors or by directly modulating the activities of mitochondrial pro- and antiapoptotic proteins through distinct phosphorylation events. This review analyses our present understanding of the role of JNK in apoptotic signaling and the various mechanisms by which JNK promotes apoptosis.Oncogene (2008) 27, 6245–6251; doi:10.1038/onc.2008.301 [ABSTRACT FROM AUTHOR]

Hematopoiesis is the cumulative result of intricately regulated signaling pathways that are mediated by cytokines and their receptors. Proper culmination of these diverse pathways forms the basis for an orderly generation of different cell types. Recent studies conducted over the past 10–15 years have revealed that hematopoietic cytokine receptor signaling is largely mediated by a family of tyrosine kinases termed Janus kinases (JAKs) and their downstream transcription factors termed STATs (signal transducers and activators of transcription). Aberration in these pathways, such as that caused by the recently identified JAK2V617F mutation, is an underlying cause for diseases such as leukemias and other myeloproliferative disorders. This recent discovery, when coupled with the fact that STATs are activated by oncoproteins such as BCR-ABL, underscores the importance of the JAK-STAT pathway in both normal cellular development and disease states.Oncogene (2007) 26, 6724–6737; doi:10.1038/sj.onc.1210757 [ABSTRACT FROM AUTHOR]

Signature abnormalities in the cell cycle and apoptotic pathway have been identified in mantle cell lymphoma (MCL), affording the opportunity to develop targeted therapies. In this study, we tested a novel class of kinase inhibitors, styryl sulfones, which differ from prior cell cycle inhibitors in that they are not related to purines or pyrimidines. We observed that two closely related compounds, ON013100 and ON01370, altered the growth and cell cycle status of MCL lines and potently inhibited the expression of several important molecules, including cyclin-dependent kinase4, p53, mouse double minute 2 (MDM2), and cyclin D as well as increased cyclin B expression. Using both terminal deoxy transferase uridine triphosphate nick end-labelling and poly ADP-ribose polymerase assays, we found that these compounds caused apoptosis in MCL cells. In addition, using molecular analyses, we observed the modulation of caspase-3 activity but not the expression of B-cell lymphoma family molecules. Next, we investigated the cytotoxicity of the MCL lines upon treatment with styryl sulfone compounds in combination with other currently used chemotherapeutic agents, such as doxorubicin (DOX) or vincristine (VCR). We found that the combination of DOX plus styryl sulfone or VCR plus styryl sulfone increased cytotoxicity by one log scale, compared with the single styryl sulfone compound. Thus, styryl sulfones alone, or in combination with chemotherapeutic agents, present attractive opportunities for new drug development in MCL.Oncogene (2007) 26, 5635–5642; doi:10.1038/sj.onc.1210350; published online 19 March 2007 [ABSTRACT FROM AUTHOR]

An experiment was conducted to study the benefits of dietary supplementation of moringa (Moringa oleifera) leaf meal (MLM) and pomegranate (Punica granatum) peel meal (PPM) on the performance, carcass attributes, immune and antioxidant responses in commercial broiler chickens during 1–42 days of age. In total, 450 Cobb-400 broiler male chicks raised in wire-floor stainless-steel battery brooder pens in an open-side poultry house were divided into five experimental groups with 18 replicates of five chicks each and fed a standard control diet (CD) and the test diets supplemented with MLM (500 and 1000 mg/kg) or PPM (250 and 500 mg/kg), each at two different concentrations. Bodyweight gain, feed conversion efficiency and carcass attributes were not affected (P > 0.05). The cell-mediated immune response to phytohaemagglutinin phosphate was not influenced (P > 0.05), but the antibody titre against Newcastle disease (ND) vaccine was significantly (P < 0.05) improved by supplementation of MLM or PPM in broiler diet at 42 days of age. However, at 21 days of age, the ND titre was similar in broilers fed CD and 500 mg/kg PPM fed group. Activities of glutathione reductase and super oxide dismutase in liver were not influenced (P > 0.05), while lipid peroxidation (LP) reduced significantly (P < 0.05) with the herbal additives. The LP in the PPM group was significantly (P < 0.05) lower than that in groups fed MLM. The activity of glutathione peroxidase (GSHPx) was significantly (P < 0.05) improved in the PPM group. Activities of antioxidant enzymes (super oxide dismutase, glutathione reductase, GSHPx) in spleen were not influenced (P > 0.05). The degree of LP in the 500 mg/kg PPM group was significantly (P < 0.05) lower than that in groups fed the CD. It is concluded that supplementation of MLM (500 and 1000 mg/kg) or PPM (250 and 500 mg/kg) in diets improved humoral immune response (against ND vaccine) at 42 days of age and reduced LP in liver in commercial broilers, without showing any negative effects on performance and carcass attributes. Supplementation of PPM (250 and 500 mg/kg) significantly improved the activity of GSHPx in the liver of broiler chickens. Stress is the main factor limiting the performance and immunity in intensively reared broiler chickens. The ill effects of stress can be minimised through fortifying their diet with natural herbal derivatives. Broiler diets were supplemented with moringa leaf meal and pomegranate peel meal, which reduced stress and improved immunity. Supplementation of moringa leaf meal and pomegranate peel meal improved immunity and reduced stress in broilers. [ABSTRACT FROM AUTHOR]

1. An experiment was conducted to study the effect of supplementing higher concentrations (100% vs. 110%) of critical amino acids (CAA) on performance (body weight gain - BWG, feed efficiency - FE), slaughter variables and nitrogen retention in broiler chicken (1-6 weeks of age) fed graded levels of toasted guar meal (TGM) as a protein source in diets. 2. The TGM was included at five graded concentrations (0, 50, 100, 150 and 200 g/kg) in iso-caloric and iso-protein diets with either the recommended concentration (100%) of CAA (lysine, total sulphur amino acids, threonine, tryptophan and valine) or at 10% higher (110%) concentration. A metabolism trial of 3-day duration was conducted during 6th week of age to study nitrogen retention. 3. The TGM levels and CAA concentration at 21 or 42 d of age did not influence BWG, FI and FE. BWG was not affected with inclusion of TGM up to 100 g/kg in starter and overall production (1-42 d of age) phases. The FE improved with TGM supplementation during starter phase, while at the end of experiment (42 d), FE was depressed by inclusion of TGM in dose dependant manner. All performance variables improved with increase in concentration of CAA from 100% to 110%. 4. Breast meat weight improved and abdominal fat weight reduced with higher levels of CAA in diet. Retention of nitrogen reduced with increase in level of TGM in broiler diet. Increasing concentrations of CAA in diet improved nitrogen retention. 5. It was concluded that TGM could be incorporated up to 100 g/kg with 100% CAA and up to 150 g/kg with 110% CAA without affecting performance. Increasing CAA concentration (110%) in diets significantly improved BWG and FE (21 and 42 d), breast meat weight and nitrogen retention in broiler chicken. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is characterized by the uncontrolled overexpression of cyclin D1. Styryl sulfonyl compounds have shown potent antitumor activity against MCL by inducing cell-cycle arrest and apoptosis. However, the exact molecular mechanism by which these compounds function is yet to be elucidated. Here, we show that the prototypical styryl sulfonyl compound ON 01910.Na decreased cyclin D1 and c-Myc protein levels in MCL cells, whereas mRNA levels of cyclin D1 were minimally affected. Notably, ON 01910.Na suppressed eukaryotic translation initiation factor 4E (eIF4E)-mediated cyclin D1 mRNA translation, decreased levels of phosphorylated Akt, mammalian target of Rapamycin (mTOR) and eIF4E-binding protein (eIF4E-BP), lowered the cap site binding activity of eIF4E and directly inhibited activity of phosphatidylinositol-3 kinase (PI-3K). Analysis of apoptotic signaling pathways revealed that ON 01910.Na induced the release of cytochrome c from mitochondria, altered expression of Bcl-2 family of proteins and stimulated activation of caspases. Taken together, styryl sulfonyls can cause a rapid decrease of cyclin D1 by blocking cyclin D1 mRNA translation through inhibition of the PI-3K/Akt/mTOR/eIF4E-BP signaling pathway and triggering a cytochrome c-dependent apoptotic pathway in MCL cells.Oncogene (2009) 28, 1518–1528; doi:10.1038/onc.2008.502; published online 9 February 2009 [ABSTRACT FROM AUTHOR]

The pupose of this study was to evaluate the activity of ON 01910.Na, a mitotic inhibitor, in in vitro and in vivo models of pancreatic cancer and to discover biomarkers predictive of efficacy. Successive in vitro and in vivo models were used; these included cell line-derived and patient-derived tumors from our PancXenoBank, a live collection of freshly generated pancreatic cancer xenografts. ON 01910.Na showed equivalent activity to gemcitabine against pancreatic cancer cell lines in vitro. The activity of the agent correlated with suppression of phospho-CDC25C and cyclin B1. These markers were optimized for a fine-needle aspirate ex vivo rapid assay. Cyclin B1 mRNA evaluation yielded the most optimal combination of accuracy and reproducibility. Next, nine patient-derived tumors from the PancXenoBank were profiled using the assay developed in cell lines and treated with ON01910.Na for 28 days. Two cases were cataloged as potential responders and seven as resistants. There was a correlation between the ex vivo assay and sensitivity to the tested agent, as the two cases prospectively identified as sensitive met prespecified criteria for response. Of the seven tumors of predictive resistant, only one was found to be sensitive to ON 01910.Na. In addition, there was a good correlation between cyclin B1 downregulation ex vivo and changes in cyclin B1 protein post-treatment. The novel mitotic inhibitor, ON 01910.Na, showed activity in preclinical model of pancreatic cancer. A rapid assay was rationally developed that not only identified cases sensitive to ON 01910.Na, but also anticipated the pharmacodynamic events occurring after in vivo exposure.Oncogene (2009) 28, 610–618; doi:10.1038/onc.2008.424; published online 24 November 2008 [ABSTRACT FROM AUTHOR]

Cyclooxygenase-2 (COX-2) inhibitors are promising anticancer agents but their long-term use at high doses is associated with adverse cardiovascular events. The molecular mechanisms underlying the anticancer or toxic cardiovascular effects of COX-2 inhibitors remain unknown. Here we report that COX-2-selective celecoxib and a novel COX-2 inhibitor ON09310 upregulate death receptor 5 (DR5) and cooperate with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), the ligand for DR5, to induce apoptosis in COX-2-positive and -negative cancer cells. We also show that both agents engage GADD153/CHOP to transcriptionally upregulate DR5 expression; GADD153/CHOP is a C/EBP homologous transcription factor implicated in cellular stress response and apoptosis. Based on our results, we propose that (1) these agents appear to mediate their effects, at least in part, by engaging GADD153/CHOP to activate DR5-dependent apoptotic pathway and (2) their regulation of GADD153/CHOP and DR5 expression appears to occur independent of their COX-2 inhibitory effects. Our results also indicate that ON09310 is generally more potent than celecoxib and, at lower concentration, strongly cooperates with TRAIL to induce apoptosis. Taken together, our findings form the basis for future in-depth studies to further explore the utility of TRAIL and/or agonistic anti-DR5 antibodies in combination with low-dose COX-2 inhibitors as a rational approach for cancer prevention and treatment.Oncogene (2008) 27, 2656–2660; doi:10.1038/sj.onc.1210894; published online 29 October 2007 [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are critical for the initiation, propagation, and treatment resistance of multiple cancers. Yet functional interactions between specific signaling pathways in solid organ "cancer stem cells," such as those of the liver, remain elusive. We report that in regenerating human liver, two to four cells per 30,000- 50,000 cells express stem cell proteins Stat3, Oct4, and Nanog, along with the prodifferentiation proteins TGF-β-receptor type II (TBRII) and embryonic liver fodrin (ELF). Examination of human hepatocellular cancer (HCC) reveals cells that label with stem cell markers that have unexpectedly lost TBRII and ELF. eIf+/- mice spontaneously develop HCC; expression analysis of these tumors highlighted the marked activation of the genes involved in the IL-6 signaling pathway, including lL-6 and Stat3, suggesting that HCC could arise from an IL-6-driven transformed stem cell with inactivated TGF-β signaling. Similarly, suppression of lL-6 signaling, through the generation of mouse knockouts involving a positive regulator of IL-6, Inter-alpha-trypsin inhibitor-heavy chain-4 (ITIH4), resulted in reduction in HCC in eIf+/- mice. This study reveals an unexpected functional link between lL-6, a major stem cell signaling pathway, and the TGF-β signaling pathway in the modulation of mammalian HCC, a lethal cancer of the foregut. These experiments suggest an important therapeutic role for targeting lL-6 in HCCs lacking a functional TGF-β pathway. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β (TGF-β) signaling members, TGF-β receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf+/− mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (P<0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-β signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.Oncogene (2007) 26, 7103–7110; doi:10.1038/sj.onc.1210513; published online 4 June 2007 [ABSTRACT FROM AUTHOR]

Mitogen-activated protein kinases (MAPKs) regulate critical signaling pathways involved in cell proliferation, differentiation and apoptosis. Recent studies have shown that a novel class of scaffold proteins mediates the structural and functional organization of the three-tier MAPK module. By linking the MAP3K, MAP2K and MAPK into a multienzyme complex, these MAPK-specific scaffold proteins provide an insulated physical conduit through which signals from the respective MAPK can be transmitted to the appropriate spatiotemporal cellular loci. Scaffold proteins play a determinant role in modulating the signaling strength of their cognate MAPK module by regulating the signal amplitude and duration. The scaffold proteins themselves are finely regulated resulting in dynamic intra- and inter-molecular interactions that can modulate the signaling outputs of MAPK modules. This review focuses on defining the diverse mechanisms by which these scaffold proteins interact with their respective MAPK modules and the role of such interactions in the spatiotemporal organization as well as context-specific signaling of the different MAPK modules.Oncogene (2007) 26, 3185–3202. doi:10.1038/sj.onc.1210411 [ABSTRACT FROM AUTHOR]

We previously demonstrated that Jak3 is a primary response gene for G-CSF and ectopic overexpression of Jak3 can accelerate granulocytic differentiation of normal mouse bone marrow cells induced by G-CSF and GM-CSF. To gain insight into the regulation of G-CSF-induced transcription of Jak3, we constructed deletion and linker scanning mutants of the Jak3 promoter sequences and performed luciferase reporter assays in the murine myeloid cell line 32Dcl3, with and without G-CSF stimulation. These experiments showed that mutation of a −67 to −85 element, which contained a putative Sp1 binding site, or mutation of a −44 to −53 GAS element resulted in a marked reduction of Jak3 promoter activity. Electrophoretic mobility shift assays revealed that Sp1 and Stat3 present in nuclear lysates of 32Dcl3 cells stimulated with G-CSF can bind to the −67 to −85 element and −44 to −53 GAS element, respectively. In addition, cotransfection of a constitutively active mutant of Stat3 along with a Jak3 promoter/luciferase reporter resulted in enhanced Jak3 promoter activity. Together, these results demonstrate that activation of Jak3 transcription during G-CSF- induced granulocytic differentiation is mediated by the combined action of Sp1 and Stat3, a mechanism also shown to be important in IL-6-induced monocytic differentiation.Oncogene (2006) 25, 2489–2499. doi:10.1038/sj.onc.1209280; published online 6 March 2006 [ABSTRACT FROM AUTHOR]

Inactivation of the transforming growth factor-β (TGF-β) pathway occurs often in malignancies of the gastrointestinal (GI) system. However, only a fraction of sporadic GI tumors exhibit inactivating mutations in early stages of cancer formation, suggesting that other mechanisms play a critical role in the inactivation of this pathway. Here, we show a wide range of GI tumors, including those of the stomach, liver and colon in elf+/− and elf+/−/Smad4+/− mutant mice. We found that embryonic liver fodrin (ELF), a β-Spectrin originally identified in endodermal stem/progenitor cells committed to foregut lineage, possesses potent antioncogenic activity and is frequently inactivated in GI cancers. Specifically, E-cadherin accumulation at cell–cell contacts and E-cadherin-β-catenin-dependent epithelial cell–cell adhesion is disrupted in elf+/−/Smad4+/− mutant gastric epithelial cells, and could be rescued by ectopic expression of full-length elf, but not Smad3 or Smad4. Subcellular fractionation revealed that E-cadherin is expressed mainly at the cell membrane after TGF-β stimulation. In contrast, elf+/−/Smad4+/− mutant tissues showed abnormal distribution of E-cadherin that could be rescued by overexpression of ELF but not Smad3 or Smad4. Our results identify a group of common lethal malignancies in which inactivation of TGF-β signaling, which is essential for tumor suppression, is disrupted by inactivation of the ELF adaptor protein.Oncogene (2006) 25, 1871–1886. doi:10.1038/sj.onc.1209211; published online 14 November 2005 [ABSTRACT FROM AUTHOR]

To localize the regulatory elements in the human follicle-stimulating hormone receptor (FSH-R) promoter/enhancer and to determine the role of upstream stimulating factors (USFs) in these elements, we transiently transfected constructs of FSH-R promoter/enhancer in pGL3 luciferase reporter plasmids into Chinese hamster ovary cells and the activities were determined by measuring luciferase luminescence of the cell lysates. The 5'-flanking regions of the human FSH-R gene from nt -1485 to -1 with respect to the gene translation start site were amplified by polymerase chain reaction (PCR) and subcloned in pGL3. Deletion mutants were created using PCR or restriction enzyme digestion. Mutation in the E-box sequence from nt -124 to -119 (E-box 3), in the construct from -224 to nt -1 or in the Inr element, which encompasses the transcriptional start site at nt -99, resulted in a substantial reduction in the human FSH-R promoter/enhancer activity. Overexpression of upstream stimulating factor-1 (USF1) suppresses the activity of the human FSH-R promoter/enhancer via Inr and E-box elements. Upstream stimulating factor-2 (USF2) decreases FSH-R promoter/enhancer activity by acting on E-box 3. The results indicate that E-box 3 and the Inr element are important elements of the human FSH-R promoter/enhancer. USF family members inhibit FSH-R gene activity by acting via these elements. USF1 and USF2 suppress human FSH-R promoter/enhancer activity by acting on E-box 3. USF1 also decreases activity by interacting with the Inr element. [ABSTRACT FROM AUTHOR]