G-protein signaling: back to the future

Heterotrimeric G-proteins are intracellular partners of G-protein-coupled receptors (GPCRs). GPCRs act on inactive Gα·GDP/Gβγ heterotrimers to promote GDP release and GTP binding, resulting in liberation of Gα from Gβγ. Gα·GTP and Gβγ target effectors including adenylyl cyclases, phospholipases and ion channels. Signaling is terminated by intrinsic GTPase activity of Gα and heterotrimer reformation — a cycle accelerated by ‘regulators of G-protein signaling’ (RGS proteins). Recent studies have identified several unconventional G-protein signaling pathways that diverge from this standard model. Whereas phospholipase C (PLC) β is activated by Gαq and Gβγ, novel PLC isoforms are regulated by both heterotrimeric and Ras-superfamily G-proteins. An Arabidopsis protein has been discovered containing both GPCR and RGS domains within the same protein. Most surprisingly, a receptor-independent Gα nucleotide cycle that regulates cell division has been delineated in both Caenorhabditis elegans and Drosophila melanogaster. Here, we revisit classical heterotrimeric G-protein signaling and explore these new, non-canonical G-protein signaling pathways

Prognostic effect of serum and tissue YKL-40 levels in bladder cancer.

OBJECTIVES: YKL-40 is a novel inflammatory serum protein shown to be associated with the presence and prognosis of several malignancies. However, its prognostic relevance has not yet been analyzed in bladder cancer (BC). Therefore, the aim of this study was to assess the tissue, serum, and urinary levels of YKL-40 and their prognostic value in BC. METHODS AND MATERIALS: YKL-40 gene expression levels were analyzed in frozen tissue samples of 91 patients with BC; YKL-40 concentrations were measured in 120 serum (101 patients with BC and 19 controls) and 154 urine samples (125 patients with BC and 29 controls). In 16 cases, corresponding serum samples collected before and after radical cystectomy were analyzed for YKL-40. Results were correlated with clinicopathological parameters and follow-up data. RESULTS: YKL-40 gene expressions and serum concentrations were higher in patients with BC compared with controls; however, urinary YKL-40 levels remained under the detection limit in both patients and controls. Higher tissue gene expressions and serum concentrations were associated with poor patients' survival in the univariable analysis (P = 0.037 and 0.022, respectively), but only high YKL-40 serum levels proved to be independent prognostic factors in BC (hazard ratio = 1.755, 95% CI: 1.014-3.039, P = 0.045). We found no significant difference between preoperative and postoperative serum concentrations of YKL-40. CONCLUSIONS: YKL-40 serum levels are associated with the presence of BC and poor patients' survival. The independent prognostic relevance of YKL-40 is of particular interest in patients with muscle-invasive BC treated with radical surgery. Our data suggest that BC tissue is not the main source of serum YKL-40 levels

Circulating and tissue expression levels of YKL-40 in renal cell cancer

PURPOSE: Blood levels of YKL-40 are elevated in various malignancies and other inflammatory diseases. Moreover, higher YKL-40 levels, have consequently been shown to correlate with poor prognosis in several cancers. The aim of this study was to investigate the prognostic value of circulating and tissue levels of YKL-40 in renal cell cancer (RCC). PATIENTS AND METHODS: Preoperative YKL-40 serum/plasma levels were determined in 222 surgically treated RCC patients, as well as in 35 controls. Postoperative serum samples were analysed in 19 of the 222 RCC cases. Moreover, gene expression levels were assessed in 101 RCC frozen tissue samples using quantitative RT real-time PCR. Finally, immunohistochemical analysis was done in 37 RCC cases to assess the tissue localization of YKL-40. Results were correlated with clinicopathological and follow-up data. RESULTS: YKL-40 serum but not tissue gene expression levels were higher in RCC patients compared to controls (p= 0.050). Serum YKL-40 levels significantly increased following nephrectomy (p< 0.001). High circulating YKL-40 concentrations were independently associated with shorter survival in both serum and plasma cohorts. YKL-40 gene expression was not correlated with patients' prognosis. CONCLUSIONS: Preoperative elevated circulating levels of YKL-40 predict survival in patients treated with nephrectomy for RCC independently of determining from serum or plasma. Tumour cells do not seem to be the main source of elevated serum/plasma YKL-40 levels in RCC patients