Cytoplasmic polyadenylation element binding protein (CPEB)1 and 2 bind to the HIF-1α mRNA 3'UTR and modulate HIF-1 α protein expression

International audienceThe heterodimeric hypoxia-inducible factor (HIF)-1 is a transcriptional master regulator of several genes involved in mammalian oxygen homeostasis. Besides a well described regulation of the HIFα-subunit via hydroxylation-mediated protein stability in hypoxia, there are several indications for an additional translational control of the HIF-1α mRNA especially after growth factor stimulation. We identified an interaction of the cytoplasmic polyadenylation element binding protein (CPEB) 1 and 2 with the 3'-UTR of the HIF-1α mRNA. Overexpression of CPEB1 and 2 affected HIF-1α protein levels mediated by its mRNA 3'-UTR. Stimulation of neuroblastoma SK-N-MC cells with insulin and thus activation of endogenous CPEBs increased the expression of a luciferase reporter gene that was fused to the 3'-UTR of HIF-1α as well as endogenous HIF-1α protein levels. This could be abrogated by treating the cells with CPEB1 or CPEB2 siRNAs. Injection of HIF-1α cRNA in Xenopus oocytes verified the elongation of the polyA tail by cytoplasmic polyadenylation. Thus, CPEB1 and 2 are involved in the regulation of HIF-1α following insulin stimulation

Hypoxia-inducible factor prolyl hydroxylase 2 (PHD2) is a direct regulator of epidermal growth factor receptor (EGFR) signaling in breast cancer

Abstract Clinical studies in breast cancer suggest important associations between intratumoral hypoxia, the upregulation of epidermal growth factor receptor (EGFR or HER1), hypoxia-inducible factor 1α (HIF-1α), and reduced patient survival. However, direct molecular links between EGFR and the hypoxia signaling system are not yet established. Since the oxygen sensor hypoxia-inducible factor prolyl hydroxylase 2 (PHD2) is considered to be the main HIF-1α regulator, we hypothesized that PHD2 and EGFR may be interconnected at the molecular level. By analyzing samples from 313 breast cancer patients, we found that EGFR is a first clinicopathological parameter positively correlating with PHD2. Mechanistically, we identified PHD2 as a direct binding partner of EGFR and show that PHD2 regulates EGFR stability as well as its subsequent signaling in breast carcinoma cells. Overall, we introduce for the first time the direct crosstalk between the oxygen sensor PHD2 and EGFR-mediated tumorigenesis in breast cancer

Epigenetic gene expression links heart failure to memory impairment

Abstract In current clinical practice, care of diseased patients is often restricted to separated disciplines. However, such an organ‐centered approach is not always suitable. For example, cognitive dysfunction is a severe burden in heart failure patients. Moreover, these patients have an increased risk for age‐associated dementias. The underlying molecular mechanisms are presently unknown, and thus, corresponding therapeutic strategies to improve cognition in heart failure patients are missing. Using mice as model organisms, we show that heart failure leads to specific changes in hippocampal gene expression, a brain region intimately linked to cognition. These changes reflect increased cellular stress pathways which eventually lead to loss of neuronal euchromatin and reduced expression of a hippocampal gene cluster essential for cognition. Consequently, mice suffering from heart failure exhibit impaired memory function. These pathological changes are ameliorated via the administration of a drug that promotes neuronal euchromatin formation. Our study provides first insight to the molecular processes by which heart failure contributes to neuronal dysfunction and point to novel therapeutic avenues to treat cognitive defects in heart failure patients