CCAAT/enhancer-binding proteins are key regulators of human type two deiodinase expression in a placenta cell line.

An appropriate concentration of intracellular T(3) is a critical determinant of placenta development and function and is mainly controlled by the activity of type II deiodinase (D2). The levels of this enzyme are finely regulated in different tissues by coordinated transcriptional mechanisms, which rely on dedicated promoter sequences (e.g. cAMP response element and TATA elements) that impart inducibility and tissue specificity to Dio2 mRNA expression. Here we show that CCAAT enhancer-binding proteins α and ß (C/EBPα and C/EBPß) promote Dio2 expression in the trophoblastic cell line JEG3 through a conserved CCAAT element, which is a novel key component of the Dio2 promoter code that confers tissue-specific expression of D2 in these cells. Increased C/EBPs levels potently induce Dio2 transcription, whereas their ablation results in loss of Dio2 mRNA. By measuring the activity of several deletion and point mutant promoter constructs, we have identified the functional CCAAT element responsible for this effect, which is located in close proximity to the most 5' TATA box. Notably, this newly identified sequence is highly conserved throughout the species and binds in vivo and in vitro C/EBP, indicating the relevance of this regulatory mechanism. Together, our results unveil a novel mechanism of regulation of D2 expression in a trophoblastic cell line, which may play a relevant role during placenta development.

The coactivator CRTC1 promotes cell proliferation and transformation via AP-1.

Regulation of gene expression in response to mitogenic stimuli is a critical aspect underlying many forms of human cancers. The AP-1 complex mediates the transcriptional response to mitogens, and its deregulation causes developmental defects and tumors. We report that the coactivator CRTC1 cyclic AMP response element-binding protein (CREB)-regulated transcription coactivator 1 is a potent and indispensable modulator of AP-1 function. After exposure of cells to the AP-1 agonist 12-O-tetradecanoylphorbol-13-acetate (TPA), CRTC1 is recruited to AP-1 target gene promoters and associates with c-Jun and c-Fos to activate transcription. CRTC1 consistently synergizes with the proto-oncogene c-Jun to promote cellular growth, whereas AP-1-dependent proliferation is abrogated in CRTC1-deficient cells. Remarkably, we demonstrate that CRTC1-Maml2 oncoprotein, which causes mucoepidermoid carcinomas, binds and activates both c-Jun and c-Fos. Consequently, ablation of AP-1 function disrupts the cellular transformation and proliferation mediated by this oncogene. Together, these data illustrate a novel mechanism required to couple mitogenic signals to the AP-1 gene regulatory program.

Chronic unexplained anaemia in isolated autoimmune thyroid disease or associated with autoimmune related disorders.

OBJECTIVE: The prevalence of chronic unexplained anaemia was analysed in patients with autoimmune thyroid disease (ATD). DESIGN: The presence of chronic unexplained anaemia, defined as anaemia not related to evident or occult bleeding and/or to erythropoietic disorders, was retrospectively assessed and compared in patients with nonautoimmune thyroid disease (NATD) and in patients with ATD. SUBJECTS AND MEASUREMENTS: Biochemical and morphological parameters of anaemia were investigated and characterized in 1643 consecutive Caucasian outpatients with thyroid disease. In 991 patients, thyroid disease had a nonautoimmune origin. ATD was diagnosed in 652 patients (71 had Graves' disease and 581 had Hashimoto's thyroiditis and its variants). In 145 patients ATD was associated with other autoimmune disorders. RESULTS: The presence of chronic unexplained anaemia was diagnosed in 123 patients (7.5%). Forty-eight had a thalassaemic trait, representing 2.9% of the whole sample. A true chronic unexplained anaemia was recorded in 75/1643 (4.6%). The occurrence of unexplained anaemia was similar in patients with NATD (1.9%) and in those with isolated ATD (2.96%; P = NS) but increased in patients with ATD and autoimmune related disorders (ARD) compared to patients with isolated ATD and/or with NATD (28.3%; both P < 0.0001; RR = 9.56 and 14.75, respectively). Chronic unexplained anaemia was virtually absent in hyperthyroid patients and was more prevalent in hypothyroid than in euthyroid patients with ATD (P = 0.0047; RR = 2.104). CONCLUSIONS: These results indicate that the increased frequency of chronic anaemia in patients with ATD is essentially due to the presence of concomitant autoimmune gastrointestinal diseases.