Abstract
TNF-alpha plays a variety of biological functions such as apoptosis, inflammation and immunity. PTEN also has various cellular function including cell growth, proliferation, migration and differentiation. Thus, possible relationships between the two molecules are suggested. TNF-alpha has been known to downregulate PTEN via NF-kappaB pathway in the human colon cell line, HT-29. However, here we show the opposite finding that TNF-alpha upregulates PTEN via activation of NF-kappaB in human leukemic cells. TNF-alpha increased PTEN expression at HL-60 cells in a time- and dose-dependent manner, but the response was abolished by disruption of NF-kappaB with p65 antisense phosphorothioate oligonucleotide or pyrrolidine dithiocarbamate. We found that TNF-alpha activated the NF-kappaB pathways, evidenced by the translocation of p65 to the nucleus in TNF-alpha-treated cells. We conclude that TNF-alpha induces upregulation of PTEN expression through NF-kappaB activation in human leukemic cells.
Highlights
phosphatase and tensin homologue (PTEN) dephosphorylates the lipid second messenger, phosphoinositol 3,4,5-trisphosphate [PI(3,4,5)P3], a product of phosphatidylinositol 3' kinase (PI3K) activity, and negatively regulates survival signaling mediated by PI3K/protein kinase B/Akt (PI3K/PKB/ Akt) (Haas-Kogan et al, 1998; Maehama and Dixon, 1998; Hwang et al, 2005)
In the present study we show that TNF- -induced PTEN expression is dependent on Nuclear transcription factor -B (NF- B) activation
The role of NF- B in PTEN expression is controversial; it has been reported that NF- B inhibits PTEN expression in the human colon or cervix cancer cell lines (Kim et al, 2004; Vasudevan et al, 2004), whereas our previous finding suggested that NF- B is a positive regulator of PTEN expression in HL-60 cells (Lee et al, 2005)
Summary
PTEN dephosphorylates the lipid second messenger, phosphoinositol 3,4,5-trisphosphate [PI(3,4,5)P3], a product of phosphatidylinositol 3' kinase (PI3K) activity, and negatively regulates survival signaling mediated by PI3K/protein kinase B/Akt (PI3K/PKB/ Akt) (Haas-Kogan et al, 1998; Maehama and Dixon, 1998; Hwang et al, 2005). A variety of human cancers, including brain, breast, endometrial, prostate, and kidney tumors are involved in mutations of Pten (Cantley and Neel, 1999; Simpson and Parsons, 2001). Mutations in this gene are responsible for Cowden syndrome, a multiple hamartoma condition associated with high incidence of breast, brain, and thyroid neoplasia (Cantley and Neel, 1999; Simpson and Parsons, 2001). We wished to examine effect of TNFinduced activation of NF- B on the PTEN expres-
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