RGS22, a novel cancer/testis antigen, inhibits epithelial cell invasion and metastasis.

RGS22 is a novel testis specific gene. It is located within chromosome 8q22.2, which shows high relevance with tumor chromosomal aberrations. We investigated the potential role of RGS22 in human tumorigenesis. We examined the level of RGS22 expression by tumor tissue arrays, immunohistochemistry and by analyzing the expression levels of four human esophageal cancer cell lines with different metastatic potential using western blot. In addition, we examined the role of RGS22 over-expression in the processes of invasion and metastasis using a highly metastatic cancer cell line. We show that RGS22 are expressed in many tumor types, but specific to cancers with epithelial origin and associated with cancer metastasis. In addition, we identified the association of RGS22 to tumor invasion in cancer cell lines. Over-expression of RGS22 in a highly metastatic esophageal cancer cell line causes decrease in cell migration and reduction in the invasive potential of the cells. RGS22 is over-expressed in low metastatic epithelial cancers and involved in the processes of cell migration and invasion in esophageal cancer cell lines. Therefore, RGS22 may be an important tumor suppressor gene in tumorigenesis, a potential new diagnostic and prognostic biomarker for metastasis and may translate to therapeutic opportunities for the preventive treatment of epithelial cancer metastasis.

Pasteurella multocida toxin activates Gbetagamma dimers of heterotrimeric G proteins.

The mitogenic Pasteurella multocida toxin (PMT) is a major virulence factor of P. multocida, which causes Pasteurellosis in man and animals. The toxin activates the small GTPase RhoA, the MAP kinase ERK and STAT proteins via the stimulation of members of two G protein families, G(q) and G(12/13). PMT action also results in an increase in inositol phosphates, which is due to the stimulation of PLCbeta via Galpha(q). Recent studies indicate that PMT additionally activates Galpha(i) to inhibit adenylyl cyclase. Here we show that PMT acts not only via Galpha but also through Gbetagamma signaling. Activation of Gbetagamma by PMT causes stimulation of phosphoinositide 3-kinase (PI3K) gamma and formation of phosphatidylinositol-3,4,5-trisphosphate (PIP(3)) as indicated by the recruitment of a PIP(3)-binding pleckstrin homology (PH) domain-containing protein to the plasma membrane. Moreover, it is demonstrated that Gbetagamma is necessary for PMT-induced signaling via Galpha. Mutants of Galpha(q) incapable of binding or releasing Gbetagamma are not activated by PMT. Similarly, sequestration of Gbetagamma inhibits PMT-induced Galpha-signaling.

Regulation of G protein-coupled receptor-adenylyl cyclase responsiveness in human airway smooth muscle by exogenous and autocrine adenosine.

Adenosine is a mediator of bronchoconstriction in asthmatics and is believed to mediate its effects through adenosine receptor activation in inflammatory cells. In this study, we identify human airway smooth muscle (ASM) as a direct target of adenosine. Acute exposure of human ASM cultures to adenosine receptor (AR) agonists resulted in rapid accumulation of cyclic adenosine monophosphate (cAMP) with a pharmacologic profile consistent with A(2b)AR activation. Little or no evidence of A1AR or A3AR expression was suggested on acute addition of various AR ligands, although a low level of A1ARs was identified in radioligand binding studies. Treatment with adenosine deaminase suggested that human ASM cultures secrete adenosine that feeds back on A(2b)ARs and regulates basal cAMP levels as well as a small degree of A(2b)AR, beta(2)AR, and prostaglandin E(2) receptor desensitization. When subjected to chronic treatment with AR agonists or agents that enhance accumulation of endogenous, extracellular adenosine, a dual effect of A(2b)AR desensitization and adenylyl cyclase (AC) sensitization was observed. This AC sensitization was eliminated by pertussis toxin and partially reversed by the A1AR antagonist 8-cyclopentyl-1,3-dipropylxanthine, suggesting a contributory role for the A1AR. Overexpression of A1ARs and A(2b)ARs in human ASM cultures resulted in differential effects on basal, agonist-, and AC-mediated cAMP production. These data demonstrate that human ASM is a direct target of exogenous and autocrine adenosine, with effects determined by differential contributions of A(2b) and A1 adenosine receptors that are time-dependent. Accordingly, the relative distribution and activation of AR subtypes in ASM in vivo may influence airway function in diseases such as asthma and warrant consideration in therapeutic strategies that target ARs or alter nucleotide/ nucleoside levels in the airway.