Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4-ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC.

Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer

https://lymphochip.nih.gov/Shaffer_Blimp_Immunity2002.pdf

Blimp-1 Orchestrates Plasma Cell Differentiation by Extinguishing the Mature B Cell Gene Expression Program

Profound vasoconstriction in the peripheral circulation is the normal response to conditions in which the arterial pressure is too low for adequate tissue perfusion, such as acute hemorrhagic or cardiogenic shock. In other conditions, the most frequent of which is septic shock,1,2 hypotension occurs as a result of failure of the vascular smooth muscle to constrict. Such so-called vasodilatory shock is characterized not only by hypotension due to peripheral vasodilatation but also by a poor response to therapy with vasopressor drugs. This syndrome has long attracted interest and defied understanding, but recent work on the function of vascular smooth . . .

The Pathogenesis of Vasodilatory Shock

The Role of SOCS-3 in Leptin Signaling and Leptin Resistance

https://www.cell.com/immunity/pdf/S1074-7613(02)00449-1.pdf

SOCS-1 participates in negative regulation of LPS responses.

SOCS-1/JAB/SSI-1 Can Bind to and Suppress Tec Protein-tyrosine Kinase *

Tec, Btk, Itk, Bmx, and Txk constitute the Tec family of protein tyrosine kinases (PTKs), a family with the distinct feature of containing a pleckstrin homology (PH) domain. Tec acts in signaling pathways triggered by the B cell antigen receptor (BCR), cytokine receptors, integrins, and receptor-type PTKs. Although upstream regulators of Tec family kinases are relatively well characterized, little is known of the downstream effectors of these enzymes. The yeast two-hybrid system has identified several proteins that interact with the kinase domain of Tec, one of which is now revealed to be a previously unknown docking protein termed BRDG1 (BCR downstream signaling 1). BRDG1 contains a proline-rich motif, a PH domain, and multiple tyrosine residues that are potential target sites for Src homology 2 domains. In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Efficient phosphorylation of BRDG1 by Tec required the PH and SH2 domains as well as the kinase domain of the latter. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 transcripts are abundant in the human B cell line Ramos, and the endogenous protein underwent tyrosine phosphorylation in response to BCR stimulation. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling.

https://www.pnas.org/content/pnas/96/21/11976.full.pdf

Molecular cloning of a docking protein, BRDG1, that acts downstream of the Tec tyrosine kinase

Objective: The aim was to investigate the effects of adenosine on nitric oxide (NO) synthesis in vascular smooth muscle cells. Methods: NO and cAMP synthesis was measured in confluent rat vascular smooth muscle cells in culture at passage 5–10, using Griess reagent and an enzyme immunoassay kit, respectively. The expression of inducible NO synthase mRNA was assayed by Northern blotting. Results: Incubation of cultures with interleukin-1β (10 ng/ml) for 24 h caused a significant increase in nitrite production. The interleukin-1β-induced nitrite production by vascular smooth muscle cells was significantly increased by adenosine or its stable analogue, 2-chloroadenosine, in a dose-dependent manner. The adenosine A2a receptor antagonist, KF17837, but not the A1 receptor antagonist, DPCPX, significantly inhibited 2-chloroadenosine-mediated nitrite production. The 2-chloroadenosine-induced nitrite production by interleukin-1β-stimulated cells was accompanied by increased inducible NO synthase mRNA accumulation. In the presence of dibutyryl-cAMP (1 mM), interleukin-1β-induced nitrite accumulation was further increased, but the effect of 2-chloroadenosine was not additive or synergistic. Addition of 2-chloroadenosine dose-dependently increased intracellular cAMP levels of vascular smooth muscle cells. Conclusions: These results indicate that adenosine acts on A2 receptors and augments NO synthesis in interleukin-1β-stimulated vascular smooth muscle cells, at least partially through a cAMP-dependent pathway.

/pdf/adenosine-stimulates-nitric-oxide-synthesis-in-vascular-18e4gs33e2.pdf

Ken-ichi Ohya

Papers

SOCS-1/JAB/SSI-1 Can Bind to and Suppress Tec Protein-tyrosine Kinase *

Molecular cloning of a docking protein, BRDG1, that acts downstream of the Tec tyrosine kinase

Adenosine stimulates nitric oxide synthesis in vascular smooth muscle cells

Tec and Jak2 Kinases Cooperate to Mediate Cytokine-Driven Activation of c-fos Transcription

Sak serine-threonine kinase acts as an effector of Tec tyrosine kinase.