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The Ras family of GTP-binding proteins are key transducers of extracellular signals, particularly through the mitogen-activated protein kinase (MAPK) pathway. Constitutively active forms of Ras are found in a variety of tumours, suggesting an important role for this pathway in cancer. Here we report that initial cellular exposure to oncogenic Ras chronically activated the MAPK pathway in the cytoplasm, but transiently activated the same pathway in the nucleus. Nuclear-activated extracellular signal-regulated kinase (ERK) was rapidly dephosphorylated, with consequent short-term activation of the Elk-1 transcription factor and expression of the c-fos gene. Additional experiments suggested that the regulatory mechanism involved requires the calcium-dependent protein phosphotyrosine phosphatase MAPK phosphatase-1 (MKP-1). This is the first report on the ability of Ras, in the absence of growth factors, to transiently activate the MAPK pathway in the nucleus and show an involvement of MKP-1 in nuclear ERK2 regulation. In addition we show that transient activation of the MAPK pathway is sufficient to drive chronic cell-cycle progression. We conclude that, whereas the MAPK pathway is necessary to initiate cellular proliferation and transformation, the transient nature of the MAPK pathway activation suggests the involvement of additional signalling pathway(s) regulated by Ras.

Estrogen receptors (ER), namely ER alpha and ER beta, are hormone-activated transcription factors with an important role in carcinogenesis. In the present study, we aimed at elucidating the implication of ER alpha in skin cancer, using chemicallyinduced mouse skin tumours, as well as cell lines representing distinct stages of mouse skin oncogenesis. First, using immunohistochemical staining we showed that ER alpha is markedly increased in aggressive mouse skin tumours in vivo as compared to the papilloma tumours, whereas ER beta levels are low and become even lower in the aggressive spindle tumours of carcinogen-treated mice. Then, using the multistage mouse skin carcinogenesis model, we showed that ER alpha gradually increases during promotion and progression stages of mouse skin carcinogenesis, peaking at the most aggressive stage, whereas ER beta levels only slightly change throughout skin carcinogenesis. Stable transfection of the aggressive, spindle CarB cells with a dominant negative form of ER alpha (dnER alpha) resulted in reduced ER alpha levels and reduced binding to estrogen responsive elements (ERE)-containing sequences. We characterized two highly conserved EREs on the mouse ER alpha promoter through which dnER alpha decreased endogenous ER alpha levels. The dnER alpha-transfected CarB cells presented altered protein levels of cytoskeletal and cell adhesion molecules, slower growth rate and impaired anchorage-independent growth in vitro, whereas they gave smaller tumours with extended latency period of tumour onset in vivo. Our findings suggest an implication of ER alpha in the aggressiveness of spindle mouse skin cancer cells, possibly through regulation of genes affecting cell shape and adhesion, and they also provide hints for the effective targeting of spindle cancer cells by dnER alpha .

Inflammation is a double-edged sword presenting a dual effect on cancer development, from one hand promoting tumor initiation and progression and from the other hand protecting against cancer through immunosurveillance mechanisms. Cytokines are crucial components of inflammation, participating in the interaction between the cells of tumor microenvironment. A comprehensive study of the role of cytokines in the context of the inflammation-tumorigenesis interplay helps us to shed light in the pathogenesis of cancer. In this paper we focus on the role of cytokines in the development of genomic instability, an evolving hallmark of cancer.

The p73 gene possesses an extrinsic P1 promoter and an intrinsic P2 promoter, resulting in TAp73 and Delta Nu p73 isoforms, respectively. The ultimate effect of p73 in oncogenesis is thought to depend on the apoptotic TA to antiapoptotic Delta N isoforms’ ratio. This study was aimed at identifying novel transcription factors that affect TA isoform synthesis. With the use of bioinformatics tools, in vitro binding assays, and chromatin immunoprecipitation analysis, a region extending -233 to -204 bp upstream of the transcription start site of the human p73 P1 promoter, containing conserved Sp1-binding sites, was characterized. Treatment of cells with Sp1 RNAi and Sp1 inhibitor functionally suppress TAp73 expression, indicating positive regulation of P1 by the Sp1 protein. Notably Sp1 inhibition or knockdown also reduces Delta Nu p73 protein levels. Therefore, Sp1 directly regulates TAp73 transcription and affects Delta Nu p73 levels in lung cancer. TAp73 gamma was shown to be the only TA isoform overexpressed in several lung cancer cell lines and in 26 non-small cell lung cancers, consistent with Sp1 overexpression, thereby questioning the apoptotic role of this specific p73 isoform in lung cancer.

Journal URL: http://www.sciencedirect.com/science/journal/00062954

Journal URL: http://www.jchemother.it/cgi-bin/digisuite.exe

Journal URL: http://www.sciencedirect.com/science/journal/03043835

Journal URL: http://www.anti-cancerdrugs.com http://www.lww.com/product/?0959-4973

Journal URL: http://www.spandidos-publications.com/ijo/ The nuclear phosphoprotein p53 is frequently inactivated in human cancer. Although it was previously classified as an oncoprotein, p53 has emerged as a tumor suppressor controlling cell cycle progression by regulating gene transcription. A major biochemical property of wildtype p53 is its ability to bind DNA in a sequence-specific manner. The human c-H-ras gene contains within its first intron sequences that partially match the p53 consensus binding site. We determined that these sequences represent a bona fide p53 element, since in vitro translated wild-type p53 recognized them with high affinity. Furthermore, wild-type p53 activated transcription from a reporter plasmid containing the c-H-ras element as an enhancer. These findings suggest that p53 regulates cellular growth by coordinate transcription of genes that suppress and promote cellular proliferation.

Journal URL: http://www.iiar-anticancer.org/main.php?id=2 The recombinant plasmid pBHIV-1 carrying the long terminal repeat (LTR) of the human immunodeficiency virus 1 (HIV-1), linked to the reporter chlorampenicol acetyl transferase (CAT) gene, was introduced into human and rat fibroblasts. Stable transfectants were obtained which were resistant to geneticin and expressed CAT-activity from the HTV-1 LTR. The response to TNFa was studied. It was found that, at the optimum concentration of 100 IU/ml in human and 1000 IU/ml in rat fibroblasts, the expression of CAT was stimulated by 2.1 and 2.5-fold respectively. Our findings suggest that TNF-a in physiological concentrations can transcriptionally activate the HTV-1 LTR sequences and this may play an important role in the pathogenesis of HIV infection.