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PI 3-K signaling pathway suppresses PMA-induced expression of p21WAF1/ Cip1 in human leukemia cells
Department of Experimental Research, Institute of Experimental and Clinical Medicine, Žygimantu 9, 01102 Vilnius, Lithuania.
Department of Experimental Research, Institute of Experimental and Clinical Medicine, Žygimantu 9, 01102 Vilnius, Lithuania.
Department of Developmental Biology, Institute of Biochemistry, Mokslininku 12, 08662 Vilnius, Lithuania.
Department of Experimental Research, Institute of Experimental and Clinical Medicine, Žygimantu 9, 01102 Vilnius, Lithuania.
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2007 (English)In: Molecular and Cellular Biochemistry, ISSN 0300-8177, E-ISSN 1573-4919, Vol. 302, no 1-2Article in journal (Refereed) Published
Abstract [en]

Despite the understanding of the importance of phosphoinositide 3-kinase (PI 3-K) signaling pathway in the regulation of cellular proliferation, little is known about its role during phorbol 12-myristate 13-acetate (PMA)-induced differentiation in human leukemia cells. Here, we report a novel finding that PI 3-K inhibition by LY294002 significantly increases p21WAF1/Cip1 expression in PMA-stimulated human leukemia cells NB4 and THP1. LY294002 potentiated expression of p21WAF1/Cip1 via a p53-independent mechanism and did not affect mitogen activated protein kinase (MAPK) activation. Electrophoretic mobility shift (EMSA) experiments revealed that blocking of PI 3-K was associated with increased binding of transcription factor Sp1 to the PMA-responsive sites on the p21WAF1/Cip1 promoter. Pretreatment with rapamycin, an inhibitor of mTOR kinase, decreased the expression of p21WAF1/Cip1 protein in PMA-stimulated NB4 cells. The level of PMA-induced p21WAF1/ Cip1 protein expression was lower in NB4 cells overexpressing wild type protein kinase C ? (PKC ?) compared to those transfected with empty vector or with kinase inactive PKC ?. Sp1 binding to the p21WAF1/Cip1 promoter was completely lost in a wild type PKC ? overexpressing and PMA-stimulated NB4 cells. We demonstrate that PI 3-K signaling pathway suppresses PMA-induced expression of p21WAF1/Cip1 in human leukemia cells, and that this effect is partly mediated by PKC ?. © Springer Science+Business Media, LLC 2007.

Place, publisher, year, edition, pages
2007. Vol. 302, no 1-2
Keyword [en]
Differentiation, Leukemia, p21WAF1/Cip1, Phorbol esters, PI 3-K, Protein kinase C?
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Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-48989DOI: 10.1007/s11010-007-9419-4OAI: oai:DiVA.org:liu-48989DiVA: diva2:269885
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-12

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Magnusson, Karl-Eric

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