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a b s t r a c t p53 gene expresses several protein isoforms modulating p53-mediated responses through regulation of gene expression. Here, we identify a novel p53 isoform, D160p53, lacking the first 159 residues. By knockdown experiments and site-directed mutagenesis, we show that D160p53 is encoded by D133p53 transcript using ATG160 as translational initiation site. This hypothesis is supported by endogenous expression of D160p53 in U2OS, T47D and K562 cells, the latter ones carrying a premature stop codon that impairs p53 and D133p53 protein expression but not the one of D160p53. Overall, these results show that the D133p53 transcript generates two different p53 isoforms, D133p53 and D160p53.

Interleukin-1 receptor antagonist (IL-1ra) has been shown to play a crucial role in the prevention of various inflammatory diseases. There is also convincing evidence that IL-1ra is able to counteract inflammatory effects of IL-1 members implicated in insulin resistance and diabetes. However, the use of knock-out animal models provides evidence to the contrary and the role of IL-1ra in obesity-linked anomalies remains controversial.This minireview gets an insight into recent findings on the implication of IL-1ra and its gene polymorphism in diabetes and obesity, discusses the potential dual effects of IL-1ra observed in different models, and comments on future directions.

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Edited by Masayuki MiyasakaKeywords: IL-1 Leptin Adipocytokine Breast cancer Obesity a b s t r a c t Obesity is associated with an increased risk of breast cancer. interleukin-1 (IL-1), a pro-inflammatory cytokine secreted by adipose tissue, is involved in breast cancer development. There is also convincing evidence that other adipocytokines including leptin not only have a role in haematopoiesis, reproduction and immunity but are also growth factors in cancer. Therefore, IL-1 family and leptin family are adipocytokines which could represent a major link between obesity and breast cancer progression. This minireview provides insight into recent findings on the prognostic significance of IL-1 and leptin in mammary tumours, and discusses the potential interplay between IL-1 family members and adipocyte-derived hormones in breast cancer.

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Migration stimulating factor (MSF) is a truncated oncofetal fibronectin isoform expressed by fetal and tumor-associated cells. MSF mRNA is distinguished from other fibronectin isoforms by its size (2.1 kb) and the inclusion of a specific intronic sequence at its 3V end. Initial Northern blot analysis with a MSF-specific probe indicated the presence of this 2.1-kb transcript and an additional unexpected 5.9-kb RNA present in both MSF-secreting ( fetal) and nonsecreting (adult) fibroblasts. Our investigations into the nature of these transcripts and their relationship to MSF protein secretion revealed that the 5.9-kb mRNA is a second MSF-encoding transcript. Both these mRNAs have identical coding sequence and differ only in the length of their intron-derived 3V -untranslated region (UTR). The 5.9-kb MSF mRNA is retained in the nucleus whereas the 2.1-kb mRNA is not. MSF-secreting fetal fibroblasts have significantly lower nuclear levels of the 5.9-kb mRNA and correspondingly higher cytoplasmic levels of the 2.1-kb transcript than their nonsecreting adult counterparts. Adult fibroblasts induced to secrete MSF by treatment with transforming growth factor-B1 displayed similar changes in their respective levels of MSF mRNA, but not those of a control gene. When cloned downstream of a reporter gene, only the longer 3V -UTR retained coding sequence within the nucleus. We conclude that expression of MSF protein is regulated by 3V -UTR truncation of the 5.9-kb nuclear-sequestered ''precursor'' MSF mRNA and nuclear export of mature 2.1-kb message. Inducible 3V -UTR processing represents a novel regulatory mechanism involved in cancer pathogenesis that may open new avenues for therapeutic gene delivery. (Cancer Res 2005; 65(23): 10742-9)

The aim of this study was to compare the regulation of the production of tumor necrosis factor-alpha (TNF-alpha) and secondary nitric oxide (NO) in macrophages submitted to a sequence of two stimulations. Pre-exposure for 18 h of mouse thioglycollate-elicited peritoneal macrophages to low doses (1-10 ng/ml) of lipopolysaccharide (LPS), in the presence or absence of serum, induces on one hand a desensitization (endotoxin tolerance) for secondary TNF-alpha responses to LPS and, on the other hand, a 4 fold increase (priming) of secondary NO responses. Preexposure to components from Gram-positive bacteria (lipoteichoic acid, peptidoglycan) and to a synthetic lipid structurally related to lipid A (compound M4), induced similar effects. In contrast to the desensitization for TNF-alpha secretion, the priming for NO production was not mimicked by sodium nitroprusside, a generator of NO. The results suggest that concomitant but distinct activation pathways induced by LPS and other agents can be dissociated by serum-independent modulation processes elicited by pre-exposure of the cells to LPS itself, or to other stimuli.