Untitled

Abstract

Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL), which is an aggressive form of human T-cell malignancy. The viral protein, Tax, immortalizes human T-cells and inhibits various types of apoptosis, and is thought to play crucial roles in the development of ATL. We have recently demonstrated that Tax induces the constitutive expression of the anti-apoptotic protein, Bcl-xL, in a mouse T-cell line. The mouse, however, is not a natural host of HTLV-I, and HTLV-I does not induce this malignancy in mice. We thus examined whether Tax also activates the expression of Bcl-xL in human T-cells. Expression of Tax in a human T-cell line, Jurkat, induced the expression of the Bcl-xL gene, but did not significantly affect the expression of the other apoptosis-related genes, Bcl-2 and Bax. Transient transfection assays showed that Tax stimulated human Bcl-xL promoter activity in Jurkat cells. Deletion of the two potential nuclear factor (NF)-kappaB binding sites in the human Bcl-xL promoter significantly decreased Tax-induced transactivation. In addition to NF-kappaB, Tax activates transcription through the c-AMP responsive element binding protein (CREB). Tax mutants segregating these two pathways showed that both the NF-kappaB and CREB pathways of Tax are required for maximum activation of a human Bcl-xL promoter, nevertheless, NF-kappaB alone was sufficient for that of a mouse Bcl-xL promoter. Northern blot analysis showed that all the human T-cell lines expressing Tax had higher levels of Bcl-xL mRNA than HTLV-I-uninfected ones. Furthermore, the sample from one patient with ATL expressed higher levels of Bcl-xL mRNA compared with levels from uninfected peripheral blood mononuclear cells. Our results suggest that Tax induces the expression of Bc-xL through the NF-kappaB and CREB pathways in HTLV-I-infected human T-cells, and then inhibits apoptosis, and such inhibition is necessary for the infected cells to advance to the leukemia in vivo.

Overexpression of hRFI inhibits 5-fluorouracil-induced apoptosis in colorectal cancer cells via activation of NF-κB and upregulation of BCL-2 and BCL-XL

“…Previous reports demonstrated that NF-kB is an important transcriptional regulator of Bcl-2 and Bcl-XL (Mori et al, 2001;Sevilla et al, 2001;Bharti and Aggarwal, 2002;Beinke and Ley, 2004;Panwalkar et al, 2004). NF-kB is a family of transcription factors composed of homo-and heterodimers of Rel family polypeptides: p50, p52, RelA (p65), RelB and c-Rel (Rel) (Bharti and Aggarwal, 2002;Beinke and Ley, 2004;Panwalkar et al, 2004).…”

Her-2/neu overexpression induces NF-κB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IκB-α that can be inhibited by the tumor suppressor PTEN

“…The induction of NF-kB by Ras was mediated by two pathways involving both Raf and PI3-kinase leading to the activation of the IKK complex (Arsura et al, 2000). Importantly, many other tumors have recently been shown to display constitutive activation of NF-kB (reviewed in Rayet and Gelinas, 1999), including the human cutaneous T-cell lymphoma HuT-78 (Giri and Aggarwal, 1998), Hodgkin's lymphomas (Bargou et al, 1997), melanoma (Shattuck et al, 1994) pancreatic adenocarcinoma (Wang et al, 1999), primary adult T-cell leukemia (Mori et al, 1999), and head and neck squamous cell carcinoma (Du ey et al, 1999). Furthermore, the Tax transforming protein produced by the human T-cell leukemia virus type 1 induces NF-kB activity (Mercurio et al, 1997;Sun et al, 1994) through activation of both IKK1 and IKK2 (Geleziunas et al, 1998;Sumitomo et al, 1999b).…”

Human T-cell leukemia virus type I and adult T-cell leukemia

“…ATL cells that do not express Tax also have an activated NF-kB pathway, although the mechanism of activation remains unknown (Mori et al, 1999). From this point of view, suppression of NF-kB pathway might be a good therapeutic target against ATL.…”