Previously, we have shown that TAL1 and the LIM-only protein gene (LMO) are regularly coactivated in T-cell acute lymphoblastic leukemia (T-ALL). This observation is likely to relate to the findings that TAL1 and LMO are highly synergistic in T-cell tumorigenesis in double-transgenic mice. To understand the molecular mechanisms of functional synergy between TAL1 and LMO in tumorigenesis and transcriptional regulation, we tried to identify downstream target genes regulated by TAL1 and LMO by a subtractive PCR method. One of the isolated genes, that for retinaldehyde dehydrogenase 2 (RALDH2), was regularly expressed in most of the T-ALL cell lines that coexpressed TAL1 and LMO. Exogenously transfected TAL1 and LMO, but not either alone, induced RALDH2 expression in a T-ALL cell line, HPB-ALL, not expressing endogeneous TAL1 or LMO. The RALDH2 transcripts in T-ALL were, however, mostly initiated within the second intron. Promoter analysis revealed that a GATA site in a cryptic promoter in the second intron was essential and sufficient for the TAL1-and LMO-dependent transcriptional activation, and GATA3 binds to this site. In addition, forced expression of GATA3 potentiated the induction of RALDH2 by TAL1 and LMO, and these three factors formed a complex in vivo. Furthermore, a TAL1 mutant not binding to DNA also activated the transcription of RALDH2 in the presence of LMO and GATA3. Collectively, we have identified the RALDH2 gene as a first example of direct transcriptional target genes regulated by TAL1 and LMO in T-ALL. In this case, TAL1 and LMO act as cofactors for GATA3 to activate the transcription of RALDH2.In various types of leukemia, specific recurrent chromosomal translocations are frequently observed and potential oncogenic transcription factors have been identified from the chromosomal breakpoints (46). These transcription factors are mostly involved in normal hematopoietic cell differentiation and growth. In T-cell acute lymphoblastic leukemia (T-ALL), frequent chromosomal abnormalities are found in the TAL1 (also called SCL or TCL5) locus (5, 9, 10, 14). Ectopic expression of TAL1, which is not normally expressed in T cells (44,57), is observed in ϳ60% of T-ALL patients (4). TAL1 encodes at least two alternative isoforms, full-length TAL1␣ and Nterminally truncated TAL1, having a basic helix-loop-helix (bHLH) motif found in a number of transcription factors involved in the regulation of cell differentiation (6). TAL1 dimerizes with ubiquitous bHLH E-proteins (E47, E12, and HEB) (20,22), and the heterodimers bind to the E-box motif (CANNTG), most preferably to AACAGATGGT (21). However, no downstream target genes have been identified. It is thus uncertain whether TAL1-E-protein heterodimers regulate transcription through binding to this preferred E-box.LMO1 (RBTN1 or TTG1) and LMO2 (RBTN2 or TTG2) are also genes originally identified from recurrent chromosomal breakpoints in T-ALL (7,34,49). Their expression in T-ALL is ectopic, like that of TAL1 (15,18,35,49). They encode highly related LIM-only cla...
cTo better understand the antibacterial activity of S-649266 against carbapenemase producers, its stability against clinically relevant carbapenemases was investigated. The catalytic efficiencies (k cat /K m ) of IMP-1, VIM-2, and L1 for S-649266 were 0.0048, 0.0050, and 0.024 M ؊1 s ؊1 , respectively, which were more than 260-fold lower than that for meropenem. Only slight hydrolysis of S-649266 against KPC-3 was observed. NDM-1 hydrolyzed meropenem 3-fold faster than S-649266 at 200 M.
Sixteen human T-cell lines were studied for the expression of a cell-adhesion molecule ICAM-1 and its counter-receptor LFA-1. The cell lines included 3 human T-cell-leukemia-virus-type-I (HTLV-1)-negative cell lines derived from acute lymphoblastic leukemia (ALL) and 13 HTLV-1-positive cell lines, 7 of them established from cord- or peripheral-blood T cells by in vitro transformation with HTLV-1, 2 derived from HTLV-1 carriers, and 4 derived from patients with adult T-cell leukemia (ATL). In sharp contrast to a basal level of ICAM-1 in 3 HTLV-1-negative ALL cell lines, strong induction of ICAM-1 was seen in all HTLV-1-positive T-cell lines except for MT-1, one of the 4 ATL cell lines used in the present study. On the other hand, the expression of LFA-1 (CD11a and CD18) was more or less similar among the cell lines with and without HTLV-1. Interestingly, however, 3 out of 4 ATL cell lines (TL-Om1, H582, HUT102) revealed striking depression of LFA-1 expression. Several lines of evidence strongly argued against direct involvement of the viral transactivator p40tax or some autocrine cytokines in the induction of ICAM-1 in HTLV-1-positive T-cell lines. It was also found that ICAM-1 and LFA-1 were involved in syncytium formation induced in the co-culture of HTLV-1-positive and HTLV-1-negative human T-cell lines. Implications of constitutive expression of ICAM-1 for certain clinical manifestations of ATL and of depression of either ICAM-1 or LFA-1 during progression of ATL are discussed.
A cell lysate prepared from MA1O4 cells that had been infected with human rotavirus KUN strain (HRV-KUN) contained a 35-kilodalton protein capable of binding to MA104 cells. The binding of the 35-kilodalton protein was inhibited by a serotype 2-specific antiserum but not by antisera to other serotypes. Not only trypsin-treated, infectious HRV-KUN but also untreated, noninfectious virions effectively competed with the 35-kilodalton protein for the same cell surface binding sites. One monoclonal anti-VP7 (AH6) absorbed the 35-kilodalton protein from the HRV-KUN-infected cell lysate, whereas another monoclonal anti-VP7 (S2-2G10) inhibited the virions to compete with the 35-kilodalton protein for the cell surface binding sites. Both anti-VP7 (S2-2G10) and anti-VP3 (K-1532, K-376) monoclonal antibodies had the virus-neutralization activity, but only anti-VP7 inhibited virus adsorption. On the other hand, anti-VP3 monoclonal antibodies were capable of completely inhibiting the infection of preadsorbed HRV-KUN as long as virions were not yet internalized.
TAL1, which is frequently activated in T cell acute lymphoblastic leukemia (T-ALL), encodes lineage-specific basic helix-loop-helix (bHLH) proteins that bind specifically to E-box DNA motif upon dimerization with ubiquitous basic helix-loop-helix proteins E47 or E12. RBTN1 and RBTN2, also frequently activated in T-ALL, encode proteins only with tandem cysteine-rich LIM domains. We found that aberrant expression of TAL1 detected in 11 out of 14 T-ALL cell lines was invariably accompanied by that of either RBTN1 or RBTN2. Forced expression of TAL1 together with RBTN1 or RBTN2, but not TAL1 alone, strongly induced artificial reporter genes in a TAL1/RBTN-negative T-ALL cell line, HPB-ALL. Such collaborative transcriptional activity of TAL1 and RBTN was not, however, observed in non-T cell lines, suggesting further involvement of some T cellspecific cofactors. In this context, we carried out preliminary evaluation of a potential role of the T cell-specific GATA-binding protein, GATA3, in the transcriptional activity of TAL1 and RBTN. We also showed that coexpression of TAL1 and RBTN1 in HPB-ALL strongly induced TALLA1, a highly specific T-ALL marker whose positivity correlated 100% with ectopic expression of TAL1 among various T-ALL cell lines. Collectively, ectopic TAL1 and RBTN1 or -2, together with some endogenous T cell-specific cofactors like GATA3, constitute a highly collaborative set of transcription factors whose aberrant activity in T cells may lead to leukemogenesis by modulating expression of downstream genes such as TALLA1.TAL1, also called SCL or TCL5, is a gene whose aberrant activation in the T cell lineage by recurrent chromosomal translocations, t(1;14)(p32;q11) and t(1;7)(p32;q35), precise ϳ90-kilobase pair interstitial chromosomal deletions (tal d ), and yet other undefined mechanisms is implicated as the major pathway for the development of T cell acute lymphoblastic leukemia (T-ALL) 1 (1-3). TAL1 is normally expressed in erythroid, mastocytic, and megakaryocytic lineages of the hematopoietic system but not in T cells (4,5). TAL1 encodes at least two polypeptides, full-length 42-kDa TAL1␣ (amino acid residues 1-331) and 22-kDa N-terminally truncated polypeptide TAL1 (amino acid residues 176 -331) (6), both containing the basic helix-loop-helix (bHLH) motif, a DNA-binding and protein dimerization domain found in a number of transcription factors. TAL1 proteins, having no intrinsic DNA binding activity, dimerize with the ubiquitously expressed E2A gene products, E47 and E12 (7,8), and the heterodimers bind to E-box elements (CANNTG) with a preferred sequence of AACAGAT-GGT (9). By using an artificial reporter gene containing multiple copies of the optimal TAL1/E2A binding sequence, transcriptional activity of the TAL1/E47 heterodimer was examined in transiently transfected murine C3H/10T1/2 fibroblasts (10). While the E47 homodimer strongly induced the reporter gene, the TAL1/E47 heterodimer was much less active, suggesting a negative regulatory role of TAL1 (10). So far, nothing is known about ...
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