PubMed · 7611548
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D N Poller, C Hackwood. 1995. Prostatic discrimination.. https://pubmed.ncbi.nlm.nih.gov/7611548/
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The G12 subfamily of heterotrimeric G proteins, comprised of the alpha-subunits Galpha12 and Galpha13, has been implicated as a signaling component in cellular processes ranging from cytoskeletal changes to cell growth and oncogenesis. In an attempt to elucidate specific roles of this subfamily in cell regulation, we sought to identify molecular targets of Galpha12. Here we show a specific interaction between the G12 subfamily and the cytoplasmic tails of several members of the cadherin family of cell-surface adhesion proteins. Galpha12 or Galpha13 binding causes dissociation of the transcriptional activator beta-catenin from cadherins. Furthermore, in cells lacking the adenomatous polyposis coli protein required for beta-catenin degradation, expression of mutationally activated Galpha12 or Galpha13 causes an increase in beta-catenin-mediated transcriptional activation. These findings provide a potential molecular mechanism for the previously reported cellular transforming ability of the G12 subfamily and reveal a link between heterotrimeric G proteins and cellular processes controlling growth and differentiation.
The limited proteolysis of insulin-like growth factor (IGF)-binding protein (IGFBP)-3 is a key event in the regulation of endocrine bioavailability of IGFs. Here, we investigated IGFBP-3 and IGFBP-3 proteolysis in serum from patients with colorectal cancer both before and at different times following surgery. In vivo IGFBP-3 proteolysis, estimated by immunoblot analysis of IGFBP-3 fragments in serum, and in vitro IGFBP-3 protease activity of serum, estimated by a 125I-IGFBP-3 degradation assay, allowed us to identify 2 groups of patients (IGF-M vs. IGF-NM) with respect to their status for mobilizing the IGF system. In IGF-M patients, in vivo and in vitro IGFBP-3 proteolysis were significantly elevated (156% and 181% of the age-matched control pool, respectively) and accompanied by a decrease in intact IGFBP-3 (38% of the control pool). The IGFBP-3 proteolytic processing was further increased in response to surgical ablation of the tumor (mean increase 45-55%), then gradually returned to levels comparable with controls. In contrast, IGF-NM patients exhibited a minimal alteration of in vitro IGFBP-3 protease activity and even an inhibition of in vivo IGFBP-3 proteolysis, whereas intact IGFBP-3 was unaltered when compared with controls. Moreover, this pattern was not further significantly altered in response to the surgical stress. None (0/6) of the IGF-M patients vs. 70% (5/7) of the IGF-NM patients developed a metastatic disease (median duration of follow-up 26 months). Neither elevated amounts of pro-IGF-II nor presence of detectable IGFBP-3 protease inhibitors in the circulation could explain the observed suppression of IGFBP-3 proteolytic processing in IGF-NM patients. These results indicate that inhibition of IGFBP-3 proteolysis and invasive properties of cancer cells are related in colorectal cancer patients.
Accumulation of mutant p53 protein occurs frequently in human malignancies, including 40-60% of non-small cell lung carcinomas. The implications of such p53 over-expression, usually assessed by immunohistochemical techniques, for the prognosis of lung cancer patients remain undetermined. In this study, we used a time-resolved immunofluorometric assay to measure p53 protein concentrations in extracts prepared from 86 primary non-small cell lung tumours and examined the associations between p53 protein levels (corrected for total protein) and other clinico-pathologic variables, including post-surgical disease-free and overall survival. Contingency tables analysed by chi2 tests revealed no significant relationships between p53 status, defined by a median cut-off point, and patient gender, age, disease stage, histologic grade and type, lymph node extension, smoking history and administration of adjuvant chemotherapy or radiation. However, multivariate Cox proportional hazard regression analysis demonstrated a dose-response relationship between p53 concentration, expressed as a 4-level, quartile-divided variable, and increased risk of relapse (p = 0.010) and death (p = 0.016). Patients whose tumours contained p53 concentrations exceeding the median value had over 3-fold higher risk of relapse (p = 0.002) and death (p = 0.007) than those whose tumours had lower p53 concentrations. We also provide evidence suggesting that the impact of p53 on survival is greater in patients with squamous cell carcinoma than in those with adenocarcinoma. Although the latter finding needs confirmation, our results suggest that application of an immunoassay of p53 protein on non-small cell lung tumour extracts may identify patients at increased risk of unfavourable outcome.