Dysregulation Of Signal Transduction Pathways Research Articles

GSK-3 as a novel prognostic indicator in leukemia.

While leukemias represent a diverse set of diseases with malignant cells derived from myeloid or lymphoid origin, a common feature is the dysregulation of signal transduction pathways that influence leukemogeneisis, promote drug resistance, and favor leukemia stem cells. Mutations in PI3K, PTEN, RAS, or other upstream regulators can activate the AKT kinase which has central roles in supporting cell proliferation and survival. A major target of AKT is Glycogen Synthase Kinase 3 (GSK3). GSK3 has two isoforms (alpha and beta) that were studied as regulators of metabolism but emerged as central players in cancer in the early 1990s. GSK3 is unique in that the isoforms are constitutively active. Active GSK3 promotes destruction of oncogenic proteins such as beta Catenin, c-MYC, and MCL-1 and thus has tumor suppressor properties. In AML, inactivation of GSK3 is associated with poor overall survival. Interestingly in some leukemias GSK3 targets a tumor suppressor and thus the kinases can act as tumor promoters in those instances. An example is GSK3 targeting p27Kip1 in AML with MLL translocation. This review will cover the role of GSK3 in various leukemias both as tumor suppressor and tumor promoter. We will also briefly cover current state of GSK3 inhibitors for leukemia therapy.

A semi-synthetic natural product blocks collagen induced arthritis by preferentially suppressing the production of IL-6

Rheumatoid arthritis (RA), an autoimmune-inflammatory disease is characterized by dysregulation of signal transduction pathways, increased production of pro-inflammatory cytokines, enhanced leukocyte infiltration into synovial microvascular endothelium, extensive formation of hyper proliferative pannus, degradation of cartilage and bone erosion. Several compounds that abrogate cytokine production demonstrate a therapeutic effect in experimental models of arthritis. In this study, we report that a novel semi-synthetic natural product (Compound A) being a preferential IL-6 inhibitor, is efficacious in a murine model of arthritis. In vitro evaluations of pro-inflammatory cytokine production reveal that Compound A preferentially inhibits induced production of IL-6 and not TNF-α from THP-1 cells and isolated human monocytes. Furthermore, Compound A robustly inhibits the spontaneous production of IL-6 from pathologically relevant synovial tissue cells isolated from patients with active RA. In a physiologically relevant assay, Compound A selectively inhibits the activated T cell contact-mediated production of IL-6 from human monocytes. Compound A, at pharmacologically efficacious concentrations, does not significantly curtail the LPS-induced activation of p38 MAPKs. In the collagen-induced arthritis (CIA) mouse model (i) macroscopic observations demonstrate that Compound A, administered subcutaneously in a therapeutic regimen, significantly and dose-dependently inhibits disease associated increases in articular index and paw thickness; (ii) histological analyses of paw tissues reveal that Compound A prominently diminishes joint destruction, hyperproliferative pannus formation and infiltration of inflammatory cells. Collectively, these results provide direct evidence that Compound A, a novel preferential IL-6 inhibitor, suppresses collagen-induced arthritis, and may be a potential therapeutic for treating patients with active RA.

A novel mTOR inhibitor is efficacious in a murine model of colitis

Ulcerative colitis is an autoimmune-inflammatory disease characterized by increased proliferation of colonic epithelial cells, dysregulation of signal transduction pathways, elevated mucosal T cell activation, increased production of proinflammatory cytokines, and enhanced leukocyte infiltration into colonic interstitium. Several compounds that possess antiproliferative properties and/or inhibit cytokine production exhibit a therapeutic effect in murine models of colitis. Mammalian target of rapamycin (mTOR), a protein kinase regulating cell proliferation, is implicated in colon carcinogenesis. In this study, we report that a novel haloacyl aminopyridine-based molecule (P2281) is a mTOR inhibitor and is efficacious in a murine model of human colitis. In vitro studies using Western blot analysis and cell-based ELISA assays showed that P2281 inhibits mTOR activity in colon cancer cells. In vitro and in vivo assays of proinflammatory cytokine production revealed that P2281 diminishes induced IFN-gamma production but not TNF-alpha production, indicating preferential inhibitory effects of P2281 on T cell function. In the dextran sulfate sodium (DSS) model of colitis, 1) macroscopic colon observations demonstrated that P2281 significantly inhibited DSS-induced weight loss, improved rectal bleeding index, decreased disease activity index, and reversed DSS-induced shortening of the colon; 2) histological analyses of colonic tissues revealed that P2281 distinctly attenuated DSS-induced edema, prominently diminished the leukocyte infiltration in the colonic mucosa, and resulted in protection against DSS-induced crypt damage; and 3) Western blot analysis showed that P2281 blocks DSS-induced activation of mTOR. Collectively, these results provide direct evidence that P2281, a novel mTOR inhibitor, suppresses DSS-induced colitis by inhibiting T cell function and is a potential therapeutic for colitis. Given that compounds with anticancer activity show promising anti-inflammatory efficacy, our findings reinforce the cross-therapeutic functionality of potential drugs.

A Novel mTOR Inhibitor Is Efficacious in a Murine Model of Colitis

Purpose: Ulcerative colitis is an autoimmune-inflammatory disease characterized by increased proliferation of colonic epithelial cells, dysregulation of signal transduction pathways, elevated mucosal T-cell activation, increased production of pro-inflammatory cytokines (e.g., TNF-α, IFN-γ), and enhanced leukocyte infiltration into colonic interstitium. Several compounds that possess anti-proliferative activities (e.g., rapamycin and its analog everolimus; mammalian target of rapamycin (mTOR) inhibitors) and/or inhibit IFN-γ production (NCX-1015, a nitric oxide derivative of prednisolone) exhibit a therapeutic effect in murine models of colitis. In this study, we report that a novel aminopyridine based molecule (P2281) is a mTOR inhibitor and is efficacious in a murine model [the dextran sulfate sodium (DSS) model] of human colitis. Methods: Cell-based ELISAs, Western blot analysis and DSS-model of colitis were employed. Results: In vitro studies using western blot analysis and cell-based ELISA assays each showed that P2281 inhibits mTOR activity (69% inhibition of mTOR phosphorylation at 10 μM in ELISA assays). In vitro and in vivo assays of pro-inflammatory cytokine production revealed that P2281 diminishes induced IFN-γ synthesis/release (IC50: ∼20 μM) but not TNF-α synthesis/release (IC50: > 100 μM). In the disease model of colitis (i) macroscopic colon observations revealed that P2281, administered intraperitoneally, significantly inhibited DSS-induced weight loss (5.70 ± 2.4% for P2281-treated mice vs. 17.75 ± 3.07% for control mice), improved rectal bleeding index (0.42 ± 0.08 for P2281-treated mice vs. 0.67 ± 0.17 for control mice), decreased disease activity index (3.92 ± 0.8 for P2281-treated mice vs. 6.83 ± 0.76 for control mice) and reversed DSS-induced shortening of the colon (colon lengths: 11.15 ± 0.3, 6.85 ± 0.39, and 7.88 ± 0.3 cms for naïve, control and P2281-treated mice, respectively); (ii) histological analyses of colonic tissues revealed that P2281 attenuated DSS-induced edema, prominently diminished the leukocyte infiltration in the colonic mucosa and resulted in protection against DSS-induced crypt damage. Conclusion: These results provide direct evidence that P2281, a novel mTOR inhibitor, suppresses DSS-induced colitis by inhibiting synthesis/release of pro-inflammatory mediators (e.g, IFN-γ) and leukocyte infiltration, and is a potentially attractive therapeutic for colitis.

Huntingtin phosphorylation and signaling pathways that regulate toxicity in Huntington's disease

Despite an intensive research on the protein huntingtin that causes Huntington's disease, little is known about the dysregulation of signal transduction pathways and their role in the pathological process. PolyQ expansion in huntingtin causes the activation of various pathways that may participate in cell death. Of particular interest is the role of the mitogen activated protein kinases. In addition, modification of huntingtin by phosphorylation might also play an important role in the disease by modulating the toxicity of mutant polyQ-huntingtin. For instance, phosphorylation of polyQ-huntingtin at serine 421 is induced by the pro-survival pathway insulin growth factor 1/Akt leading to a decreased polyQ-huntingtin-induced cell death. Studying such neuronal survival and death pathways and their components in HD will certainly lead to a better knowledge of huntingtin function/dysfunction in disease.

Dysregulation of signal transduction pathways as a potential mechanism of nervous system alterations in HIV-1 gp120 transgenic mice and humans with HIV-1 encephalitis.

HIV-1 associated central nervous system (CNS) disease involves neuronal damage and prominent reactive astrocytosis, the latter characterized by strong upregulation of the glial fibrillary acidic protein (GFAP) in astrocytes. Similar alterations are found in transgenic mice expressing the HIV-1 envelope protein gp120 in the CNS. Because alterations of astrocyte functions could contribute to neuronal impairment, we compared brains of gp120 transgenic mice and gp120-transfected C6 astrocytoma cells with controls and found that gp120 induced a prominent elevation of steady state GFAP mRNA levels, primarily due to transcript stabilization. Increased levels of GFAP mRNA were also found in nontransfected C6 cells exposed to recombinant gp120. Exposure of C6 cells or primary mouse astrocytes to soluble gp120 led to activation of PKC as indicated by redistribution and increase in PKC immunoreactivity at the single cell level. gp120 effects were diminished by inhibitors of protein kinase C (PKC) but not inhibitors of protein kinase A. PKC activity was upmodulated in gp120-transfected C6 cells and in the CNS of gp120 transgenic mice. Further, brain tissue from patients with HIV-1 encephalitis and from gp120 transgenic mice showed increased PKC immunoreactivity. Taken together, these results indicate that gp120-induced increases in PKC activity may contribute to the gliosis seen in gp120 transgenic mice as well as in HIV-1-infected humans and raise the question of whether dysregulation of signal transduction pathways represents a general mechanism of HIV-associated pathogenesis.