TG-interacting factor 1 acts as a transcriptional repressor of sterol O-acyltransferase 2

Acat2 [gene name: sterol O-acyltransferase 2 (SOAT2)] esterifies cholesterol in enterocytes and hepatocytes. This study aims to identify repressor elements in the human SOAT2 promoter and evaluate their in vivo relevance. We identified TG-interacting factor 1 (Tgif1) to function as an important repressor of SOAT2. Tgif1 could also block the induction of the SOAT2 promoter activity by hepatocyte nuclear factor 1α and 4α. Women have ∼30% higher hepatic TGIF1 mRNA compared with men. Depletion of Tgif1 in mice increased the hepatic Soat2 expression and resulted in higher hepatic lipid accumulation and plasma cholesterol levels. Tgif1 is a new player in human cholesterol metabolism.     

The p53 tumour suppressor inhibits glucocorticoid-induced proliferation of erythroid progenitors

Hypoxia encountered at high altitude, blood loss and erythroleukemia instigate stress erythropoiesis, which involves glucocorticoid-induced proliferation of erythroid progenitors (ebls). The tumour suppressor p53 stimulates hematopoietic cell maturation and antagonizes glucocorticoid receptor (GR) activity in hypoxia, suggesting that it may inhibit stress erythropoiesis. We report that mouse fetal liver ebls that lack p53 proliferate better than wild-type cells in the presence of the GR agonist dexamethasone. An important mediator of GR-induced ebl self-renewal, the c-myb gene, is induced to higher levels in p53^–/– ebls by dexamethasone. The stress response to anemia is faster in the spleens of p53^–/– mice, as shown by the higher levels of colony forming units erythroids and the increase in the CD34/c-kit double positive population. Our results show that p53 antagonizes GR-mediated ebl expansion and demonstrate for the first time that p53–GR cross-talk is important in a physiological process in vivo: stress erythropoiesis.     

Of flies and men; p53, a tumour suppressor

The completion of the Drosophila genome sequencing project [Science 287 (2000) 2185] has reconfirmed the fruit fly as a model organism to study human disease. Comparison studies have shown that two thirds of genes implicated in human cancers have counterparts in the fly [Curr. Opin. Genet. Dev. 11 (2001) 274; J. Cell Biol. 150 (2000) F23], including the tumour suppressor, p53. The suitability of the fruit fly to study the function of the tumour suppressor p53 is further exemplified by the lack of p53 family members within the fly genome, i.e., no homologues to p63 and p73 have been identified. Hence, there is no redundancy between family members greatly facilitating the analysis of p53 function. In addition, studying p53 in Drosophila provides an opportunity to learn about the evolution of tumour suppressors. Here, we will discuss what is known about Drosophila p53 in relation to human p53.