1,721,039 research outputs found
Transcriptional regulation of the human tumor suppressor p14ARF by E2F1, E2F2, E2F3 and SP1-like factors
Full text linkThe human ARF/INK4a locus encodes two cell cycle inhibitors, p16INK4a and p14ARF, by using separate promoters. A variety of mitogenic stimuli upregulate ARF but a direct modulation at the transcriptional level has been reported only for E2F-1. We show here that the ARF promoter is strongly responsive also to E2F2 and E2F3, thus providing a strong support to their suggested role in the induction of apoptosis. Through the usage of both deletion mutants and/or site-directed mutants, we surprisingly found that none of the four putative E2F consensus sites is strictly necessary for the upregulation of ARF expression, as a minimal deletion mutant, lacking all the putative E2F binding sites, is still transactivated by E2F. Moreover, our data suggest that the ARF promoter is regulated by E2F through both direct binding to the promoter sequences and indirectly, probably by Sp1-like factors
Glucose-6-phosphate dehydrogenase (G6PD) deficiency in southern Italy: a case of G6PD A(-) associated with favism.
No full textDuring a routine screening for G6PD deficiency in the Province of Matera (Southern Italy), an eleven-year-old boy was brought to our attention who had fever obviously caused by a viral infection, but who also had hepatosplenomegaly and haemoglobinuria. The boy had previously experienced two severe haemolytic attacks. At the age of six months severe haemolysis occurred after the ingestion of cooked fava beans. At the age of seven years, the haemolytic episode was very likely triggered by oral administration of co-trimoxazole. The G6PD activity level in erythrocyte lysate was clearly defective (25% of normal). The electrophoretic mobility of G6PD was 110% of normal. These data together with those obtained from biochemical and molecular characterisation allowed the variant to be identified as G6PD A(-). This is the first report of an association between the African type G6PD deficiency variant and favism
Repression of transcriptional activity at a distance by the evolutionarily conserved KRAB domain present in a subfamily of zinc finger proteins.
No full textp63 as a new player involved in the cancer cell response to chemotherapy
No full textPoly (ADP-ribose)polymerase 1 (PARP-1) is involved in cellular processes such as DNA repair and apoptosis. Therefore, PARP-1 inhibitor (PJ34) is considered a potential treatment for p53 proficient breast and ovarian carcinoma cells, when combined with TOP I poisons.
p63 is a member of the p53 family highly expressed in carcinoma cells of epithelial origin. In particular, TAp63 proteins mimic p53 transcriptional and proapoptotic functions whereas the ???Np63?? protein has been shown to repress p53-target genes acting as an oncogene.
We have analyzed the sensitivity of MCF7 (p53wt), MDA-MB231 (p53mut ) breast carcinoma and SCC022 (p53null) squamous carcinoma cells to PJ34 and TOP I (CPT, TPT) inhibitors combined treatment. We show that MCF-7 cells exhibit apoptotic cell death while MDA-MB231 and SCC022 cells are resistant to these agents. In MCF7 cells PJ34 reverts TPT-dependent PARP-1 auto-modification and triggers caspase- dependent PARP-1 proteolysis. Furthermore, TPT as a single agent stimulates p53 expression while in combination with PJ34 also induces TAp63 proteins.
In SCC022 cells we observed that degradation of endogenous ???Np63?? by TPT+PJ34 treatment is not sufficient to induce apoptosis thereby indicating that p53 and/or TAp63 is/are required to induce apoptosis. Our data suggest that p63 is a new player in the apoptosis pathway triggered by TOP I and PARP-1 inhibitors
Repression of transcriptional activity at a distance by the evolutionarily conserved KRAB domain present in a subfamily of zinc finger proteins
No full textSub-families of related zinc finger protein genes have been defined on the basis of evolutionarily conserved structural features found outside the C2-H2 finger repeats. Such elements include the FAX domain found in a large number of Xenopus ZFPs, the evolutionarily conserved KRAB (Krüppel-associated box) and the ZiN (zinc finger N-terminal) domains. Here we describe a new evolutionarily conserved motif within zinc finger proteins which we have named the leucine rich region (LeR). Since conserved modules in regulatory proteins may specify properties relevant to their action we have determined the functional capabilities of LeR and the KRAB domains in the regulation of gene transcription by fusing relevant regions to a heterologous DNA-binding domain (GAL4 DNA-binding domain). We found that the KRAB-A domain tethered to RNA polymerase II promoters by a GAL4 DNA-binding domain actively represses transcription in a distance-independent manner. KRAB-mediated repression is dependent on the dose of the GAL4-KRAB-A fusion protein and on the presence of GAL4 binding sites on the DNA. Conversely, the LeR domain did not modulate significantly the transcription. Our results indicate that the KRAB domain present in the non-finger region of many ZFP genes quenches transcription possibly due to specific protein-protein interactions between the KRAB-A domain and components of the proximal transcriptional apparatus
“Suppression of Ras-mediated NIH3T3 transformation by p19ARF does not involve alterations of cell growth properties”.
No full text“Suppression of Ras-mediated NIH3T3 transformation by p19ARF does not involve alterations of cell growth properties”.
No full textSuppression of Ras-mediated NIH3T3 transformation by p19ARF does not involve alterations of cell growth properties
No full textSuppression of Ras-mediated NIH3T3 transformation by p19ARF does not involve alterations of cell growth properties
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