Upregulation of bfl-1 is a potential mechanism of chemoresistance in B-cell chronic lymphocytic leukaemia

B-cell chronic lymphocytic leukaemia (B-CLL) is characterised by the progressive accumulation of monoclonal CD5+ B cells. In a previous study, we have analysed the expression profile of apoptosis-regulating genes using a cDNA-based microarray and found overexpression of the antiapoptotic bcl-2 family member, bfl-1, in B-CLL cells with an apoptosis-resistant phenotype. In this study, bfl-1 mRNA levels have been determined by competitive PCR in an extended population of B-CLL patients to characterise its role in disease progression and development of chemoresistance. bfl-1 levels were significantly higher in patients with no response (NR) to last chemotherapy than in patients responding (partial response (PR)) to last chemotherapy (P<0.05) and in patients who had not required treatment (P<0.05). We found no correlation between bfl-1 mRNA levels and disease progression, IGHV mutational status or other clinical parameters. In addition, bfl-1 mRNA levels were inversely correlated with apoptotic response to in vitro fludarabine treatment of B-CLL cells. Specific downregulation of bfl-1 using siRNA induced apoptosis in resistant cells. Our data suggest that bfl-1 contributes to chemoresistance and might be a therapeutic target in B-CLL

PDGF and PDGF receptors in glioma

The family of platelet-derived growth factors (PDGFs) plays a number of critical roles in normal embryonic development, cellular differentiation, and response to tissue damage. Not surprisingly, as it is a multi-faceted regulatory system, numerous pathological conditions are associated with aberrant activity of the PDGFs and their receptors. As we and others have shown, human gliomas, especially glioblastoma, express all PDGF ligands and both the two cell surface receptors, PDGFR-α and -β. The cellular distribution of these proteins in tumors indicates that glial tumor cells are stimulated via PDGF/PDGFR-α autocrine and paracrine loops, while tumor vessels are stimulated via the PDGFR-β. Here we summarize the initial discoveries on the role of PDGF and PDGF receptors in gliomas and provide a brief overview of what is known in this field

The activation region of the Tat protein of human immunodeficiency virus type-1 functions in yeast.

The N-terminal 48 amino acids of the Tat protein of human immunodeficiency virus type (HIV)-1 constitute its activation region. This region can autonomously activate transcription when targeted to the HIV-1 long terminal repeat or certain heterologous promoters either through DNA binding sites located upstream of the transcription initiation site or via downstream RNA binding sites in mammalian cells. To determine whether the Tat activation region can function in yeast, we have assayed the effect of a chimeric gene (GAL-Tat48) expressing the DNA binding domain of the yeast transcription factor Gal4 (residues 1-147) and the activation region of Tat on GAL1 promoter-directed expression of the lacZ reporter gene in Saccharomyces cerevisiae. Our results indicate that the Gal-Tat48 fusion protein can induce significant activation of the GAL1 promoter. Analysis of a number of Tat mutants located within the activation region indicate that the amino acid residues of Tat essential for trans-activation in mammalian cells are also required for transactivation in yeast. Our results suggest that Tat-mediated transcriptional activation may involve a mechanism conserved among yeast and mammalian cells