Witold Nowak

Publications (2)10.85 Total impact

• Source

  Available from: Magdalena Kozakowska

  Article: Opposite effects of HIF-1α and HIF-2α on the regulation of IL-8 expression in endothelial cells.

  Urszula Florczyk, Szymon Czauderna, Anna Stachurska, Magdalena Tertil, Witold Nowak, Magdalena Kozakowska, Lorenz Poellinger, Alicja Jozkowicz, Agnieszka Loboda, Jozef Dulak
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  ABSTRACT: Recently we have shown that hypoxia as well as overexpression of the stable form of hypoxia-inducible factor-1α (HIF-1α) diminished the expression of interleukin-8 (IL-8) by inhibition of the Nrf2 transcription factor in HMEC-1 cells. Because HIF isoforms may exert different effects, we aimed to examine the influence of HIF-2α on IL-8 expression in endothelial cells. In contrast to HIF-1α, overexpression of HIF-2α obtained by adenoviral transduction resulted in increased expression of IL-8 in an Nrf2-independent way. Importantly, HIF-2α augmented the activity of SP-1, a transcription factor involved in IL-8 regulation and known coactivator of c-Myc. Additionally, HIF-1 decreased, whereas HIF-2 increased, c-Myc expression, and silencing of Mxi-1, a c-Myc antagonist, restored IL-8 expression downregulated by HIF-1α or hypoxia. Accordingly, binding of c-Myc to the IL-8 promoter was abolished in hypoxia. Importantly, both severe (0.5% O(2)) and mild (5% O(2)) hypoxia diminished IL-8 expression despite the stabilization of both HIF-1 and HIF-2. This study reveals the opposite roles of HIF-1α and HIF-2α in the regulation of IL-8 expression in endothelial cells. However, despite stabilization of both isoforms in hypoxia the effect of HIF-1 is predominant, and downregulation of IL-8 expression in hypoxia is caused by attenuation of Nrf2 and c-Myc.
  Free radical biology & medicine 08/2011; 51(10):1882-92. · 5.42 Impact Factor
• Source

  Available from: Magdalena Kozakowska

  Article: Effects of heme oxygenase-1 on induction and development of chemically induced squamous cell carcinoma in mice.

  Halina Was, Malgorzata Sokolowska, Aleksandra Sierpniowska, Paweł Dominik, Klaudia Skrzypek, Bozena Lackowska, Antoni Pratnicki, Anna Grochot-Przeczek, Hevidar Taha, Jerzy Kotlinowski, Magdalena Kozakowska, Andrzej Mazan, Witold Nowak, Lucie Muchova, Libor Vitek, Anna Ratajska, Jozef Dulak, Alicja Jozkowicz
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  ABSTRACT: Heme oxygenase-1 (HO-1) is an antioxidative and cytoprotective enzyme, which may protect neoplastic cells against anticancer therapies, thereby promoting the progression of growing tumors. Our aim was to investigate the role of HO-1 in cancer induction. Experiments were performed in HO-1(+/+), HO-1(+/-), and HO-1(-/-) mice subjected to chemical induction of squamous cell carcinoma with 7,12-dimethylbenz[a]anthracene and phorbol 12-myristate 13-acetate. Measurements of cytoprotective genes in the livers evidenced systemic oxidative stress in the mice of all the HO-1 genotypes. Carcinogen-induced lesions appeared earlier in HO-1(-/-) and HO-1(+/-) than in wild-type animals. They also contained much higher concentrations of vascular endothelial growth factor and keratinocyte chemoattractant, but lower levels of tumor necrosis factor-α and interleukin-12. Furthermore, tumors grew much larger in HO-1 knockouts than in the other groups, which was accompanied by an increased rate of animal mortality. However, pathomorphological analysis indicated that HO-1(-/-) lesions were mainly large but benign papillomas. In contrast, in mice expressing HO-1, most lesions displayed dysplastic features and developed to invasive carcinoma. Thus, HO-1 may protect healthy tissues against carcinogen-induced injury, but in already growing tumors it seems to favor their progression toward more malignant forms.
  Free radical biology & medicine 08/2011; 51(9):1717-26. · 5.42 Impact Factor