Investigating the physiological role of S199A and S199D mutants of PHF6 protein in T-cell acute lymphoblastic leukemia.

Background/aim: T-cell acute lymphoblastic leukemia (T-ALL) is a form of leukemia characterized by the proliferation of immature T lymphocytes. NOTCH1 is one of the most frequently mutated genes in T-ALL. NOTCH1 expression in T-cell development depends on plant homeodomain finger protein 6 (PHF6), which plays a tumor suppressor role in T-ALL.

TNFR1 signaling is positively regulated by Jak-2 and c-Src via tyrosine phosphorylation.

Background/aim: Tumor necrosis factor alpha (TNFα, a.k.a.

Positive regulation of TNFR1 signaling via SH3 recognition motif.

TNF is a pleiotropic cytokine and shows its biological function by binding to its receptors called TNFR1 and TNFR2. While TNFR1 induces apoptosis by activation of caspase-8 via the "death domain", it also activates IKKα/β, MKK3/6, MKK4/7 by activation of TAK1. Although the TNFR1 signaling pathway is known by in large, it is not known how AKT and MAPKs p38, ERK1/2, and JNK1/2 are activated.

Regulation of E2F1 activity via PKA-mediated phosphorylations.

E2F1 becomes activated during the G1 phase of the cell cycle, and posttranslational modifications modulate its activity. Activation of G-protein coupled receptors (GPCR) by many ligands induces the activation of adenylate cyclases and the production of cAMP, which activates the PKA enzyme. Activated PKA elicits its biological effect by phosphorylating the target proteins containing serine or threonine amino acids in the RxxS/T motif.

AKT-mediated phosphorylation of TWIST1 is essential for breast cancer cell metastasis.

Previously, it was shown that human TWIST1 (basic helix-loop-helix (b-HLH) is phosphorylated by Akt kinase at S42, T121, and S123. To show in vivo effect of these phosphorylations, we created mouse TWIST1 expression vector and converted the codons of S42, T125, and S127 to unphosphorylatable alanine and phosphorylation mimicking Glutamic acid. We hypothesized that alanine mutants would inhibit the metastatic ability of 4T1 cells while glutamic acid mutants would convert nonmetastatic 67NR cells into metastatic phenotype.

Negative Regulation of TNFR1 Signaling Via PKA-Mediated Phosphorylation of TNFR1.

Tumor necrosis factor alpha (TNF-α) plays a paramount role in homeostasis by inducing tumor cytotoxicity and activating immune system. The signaling complexes formed by TNFR1 to activate JNK, p38, and nuclear factor-kappa B pathways and to subsequently induce apoptosis and necroptosis are well known. However, this "canonical TNF-α signaling" does not explain how ERK, AKT, and STAT3 can be activated by TNF-α.

The regulation of circadian clock by tumor necrosis factor alpha.

All organisms display circadian rhythms which are under the control of the circadian clock located in the hypothalamus at the suprachiasmatic nucleus, (SCN). The circadian rhythms allow individuals to adjust their physiological activities and daily behavior for the diurnal changes in the living environment. To achieve these, all metabolic processes are aligned with the sleep/wake and fasting/feeding cycles.

Identification of novel mutations of Insulin Receptor Substrate 1 (IRS1) in tumor samples of non-small cell lung cancer (NSCLC): Implications for aberrant insulin signaling in development of cancer.

Lung cancer is the leading cause of cancer-related death, and NSCLC constitutes nearly 85%-90% of all cases. The IRS proteins function as adaptors and transmit signals from multiple receptors. Upon binding of insulin to the insulin receptor (IR), IRS1 is phosphorylated at several YXXM motifs creating docking sites for the binding of PI3Kp85, which activates AKT kinase.

TGF-β-SMAD-miR-520e axis regulates NSCLC metastasis through a TGFBR2-mediated negative-feedback loop.

Transforming growth factor-β (TGF-β) pathway plays crucial roles during the carcinogenesis and metastasis. TGF-β receptor 2 (TGFBR2) is a key molecule for the regulation of TGF-β pathway and frequently downregulated or lost in several cancer types including non-small cell lung cancer (NSCLC), and TGF-β pathway is often regulated by negative-feedback mechanisms, but little is known about the mechanism of TGFBR2 downregulation in NSCLC. Here, we found that the expression of miR-520e is upregulated in metastatic tumor tissues compared with non-metastatic ones, and its expression is inversely correlated with that of TGFBR2 in clinical samples.

Downregulation of SATB2 is critical for induction of epithelial-to-mesenchymal transition and invasion of NSCLC cells.

Objectives: The epithelial-to-mesenchymal transition (EMT) is considered as a key step in invasion of cancer cells. There are several regulator proteins responsible for induction of EMT, but underlying mechanisms are still unclear. SATB2 is an epigenetic regulator involved in osteoblastic differentiation.

E2F1 transcription factor and its impact on growth factor and cytokine signaling.

E2F1 is a transcription factor involved in cell cycle regulation and apoptosis. The transactivation capacity of E2F1 is regulated by pRb. In its hypophosphorylated form, pRb binds and inactivates DNA binding and transactivating functions of E2F1.

Differential expression and activation of epidermal growth factor receptor 1 (EGFR1), ERK, AKT, STAT3, and TWIST1 in nonsmall cell lung cancer (NSCLC).

Lung cancer is the leading cause of death of both men and women across the world. Overexpression and activating mutations of the epidermal growth factor receptor-1 (EGFR1) are frequently observed and associated with poor prognosis. To inhibit the function of EGFR1, multiple antibodies and small-molecule tyrosine kinase inhibitors (TKI) that target EGFR1 have been developed.

Type 1 TNF receptor forms a complex with and uses Jak2 and c-Src to selectively engage signaling pathways that regulate transcription factor activity.

The type 1 TNFR (TNFR1) contains a death domain through which it interacts with other death-domain proteins to promote cellular responses. However, signaling through death-domain proteins does not explain how TNFR1 induces the tyrosine phosphorylation of intracellular proteins, which are important to cellular responses induced by TNFR1. In this study, we show that TNFR1 associates with Jak2, c-Src, and PI3K in various cell types.

Lack of BCL-2 confers interferon-alpha sensitivity to B-cell lymphomas.

Hairy cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder with pathological manifestations usually including splenomegaly and pancytopenia. Interferons (IFNs), specifically of the alpha subtypes, have shown a significant anti-tumor effect in HCL patients, with improvement of hematological parameters within the first few months of treatment. However, the therapeutic effect of IFN-alpha is still rather limited.

Compound heterozygosity for two beta chain variants: the mildly unstable Hb Tyne (codon 5 Pro→Ser) and HbS (codon 6 Glu→Val).

Compound heterozygosity for Hb Tyne and HbS, that is very rare, was identified by direct DNA sequencing of the beta-globin gene in a Turkish patient. Hematological investigation of a girl at the age of 9 due to the presence of HbS (40.7%) led to the identification of a compound heterozygosity at codons 5-6.

Tumor necrosis factor activates CRE-binding protein through a p38 MAPK/MSK1 signaling pathway in endothelial cells.

Tumor necrosis factor (TNF) promotes immunity and modulates cell viability, in part, by promoting alterations of cellular gene expression. The mechanisms through which TNF communicates with the nucleus and alters gene expression are incompletely understood. Incubation of human umbilical vein endothelial cells (HUVEC) with TNF induces phosphorylation of the CRE-binding protein (CREB) transcription factor on serine 133 and increases CREB DNA binding and transactivation.

Suppression of TNF-alpha mediated apoptosis by EGF in TNF-alpha sensitive human cervical carcinoma cell line.

The tumor suppressor protein p53 is the most frequently mutated gene in human cancer. The function of p53 is not restricted to "guarding" against oncogenic stress, but also p53 can guard against the presence of DNA damage. One of the principal mechanisms by which cells achieve this is by regulating the p53 protein level although its phosphorylation and cellular localization also contribute to the regulation of its function.

Tumor necrosis factor-alpha-induced accumulation of tumor suppressor protein p53 and cyclin-dependent protein kinase inhibitory protein p21 is inhibited by insulin in ME-180S cells.

The tumor suppressor protein p53 plays an important role in the protection against the development of cancer and is inactivated in many human malignancies. Since p53 is an important inhibitor of cell growth, keeping p53 function under control is critical for survival of cell. One of the principal mechanisms by which cells achieve this is by regulating the p53 protein level, although its phosphorylation and cellular localization also contribute to the regulation of its function.