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Dioxin is an extremely potent carcinogen. In highly exposed people, the most commonly observed toxicity is chloracne, a pathological response of the skin. Most of the effects of dioxin are attributed to its activation of the aryl hydrocarbon receptor (AHR), a transcription factor that binds to the Ah receptor nuclear translocator (ARNT) to regulate the transcription of numerous genes, including CYP1A1 and CYP1B1. In cultures of normal human epidermal keratinocytes dioxin accelerates cell differentiation, as measured by the formation of cornified envelopes. We show that this acceleration is mediated by the AHR; also, that dioxin increases the expression of several genes known to be regulated by ARNT, which have critical roles in the cornification and epidermal barrier function of the skin. Importantly, we demonstrate that all of these responses are opposed by ligand-activation of the EGF receptor (R), an important regulator of keratinocyte cell fate. In the CYP1A1 enhancer, EGFR activation prevents recruitment of the p300 coactivator, although not affecting the binding of the AHR or ARNT. The total cellular level of p300 protein does not decrease, and overexpression of p300 relieves EGFR-mediated repression of transcription, indicating that p300 is a critical target for the repression of the AHR complex by EGFR signaling. These results provide a mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin is able to disrupt epidermal homeostasis and identify EGFR signaling as a regulator of the AHR. This signaling may modulate the incidence and severity of chloracne and be of therapeutic relevance to human poisonings by dioxin. dioxin | ARNT | psoriasis | cornification

Tumor angiogenesis and its regulation by p53-induced degradation of hypoxia-inducible factors 1 alpha are discussed. It has been shown that homozygous deletion of the p53 tumor suppressor gene using homologous recombination in a human cancer cell line promotes neovascularization and growth of tumor xenografts in nude mice. That p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1 alpha subunit of hypoxia inducible factor 1 (HIF-1). HIF-1 is a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis responding to insufficient oxygen. Amplification of normal HIF-1-dependent responses to hypoxia via loss of p53 function contributes to the angiogenic switch during tumorigenesis.

Byline: Vinhthuy Phan, Allen Thomas, Kriangsiri Malasri, Carrie Hayes Sutter We propose a novel method to estimate editing efficiency by adenosine deaminases that act on RNA (ADARs). The method employs the notion of stability of secondary structure in the vicinity of edited sites during transcription. Such an analysis of 'dynamic' structural motifs of RNA is important because as a pre-spliced RNA is being transcribed and elongated, its entire structure, and thus its local structures, may change drastically. Our simulation showed that the stability of structures in the vicinity of edited sites correlates moderately highly with editing efficiency of edited sites recently established in laboratory experiments.

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates cellular and systemic homeostatic responses to reduced [O.sub.2] availability in mammals, including angiogenesis, erythropoiesis, and glycolysis. HIF-1 activity is controlled by the [O.sub.2]-regulated expression of the HIF-1[Alpha] subunit. Under nonhypoxic conditions, HIF-1[Alpha] protein is subject to ubiquitination and proteasomal degradation. Here we report that missense mutations and/or deletions involving several different regions of HIF-1[Alpha] result in constitutive expression and transcriptional activity in nonhypoxic cells. We demonstrate that hypoxia results in decreased ubiquitination of HIF-1[Alpha] and that missense mutations increase HIF-1[Alpha] expression under nonhypoxic conditions by blocking ubiquitination.