HIF-1alpha induces cell cycle arrest by functionally counteracting Myc.

Hypoxia induces angiogenesis and glycolysis for cell growth and survival, and also leads to growth arrest and apoptosis. HIF-1alpha, a basic helix-loop-helix PAS transcription factor, acts as a master regulator of oxygen homeostasis by upregulating various genes under low oxygen tension. Although genetic studies have indicated the requirement of HIF-1alpha for hypoxia-induced growth arrest and activation of p21(cip1), a key cyclin-dependent kinase inhibitor controlling cell cycle checkpoint, the mechanism underlying p21(cip1) activation has been elusive. Here we demonstrate that HIF-1alpha, even in the absence of hypoxic signal, induces cell cycle arrest by functionally counteracting Myc, thereby derepressing p21(cip1). The HIF-1alpha antagonism is mediated by displacing Myc binding from p21(cip1) promoter. Neither HIF-1alpha transcriptional activity nor its DNA binding is essential for cell cycle arrest, indicating a divergent role for HIF-1alpha. In keeping with its antagonism of Myc, HIF-1alpha also downregulates Myc-activated genes such as hTERT and BRCA1. Hence, we propose that Myc is an integral part of a novel HIF-1alpha pathway, which regulates a distinct group of Myc target genes in response to hypoxia.

The ecology of eating: smaller portion sizes in France Than in the United States help explain the French paradox.

Part of the "French paradox" can be explained by the fact that the French eat less than Americans. We document that French portion sizes are smaller in comparable restaurants, in the sizes of individual portions of foods (but not other items) in supermarkets, in portions specified in cookbooks, and in the prominence of "all you can eat" restaurants in dining guides. We also present data, from observations at McDonald's, that the French take longer to eat than Americans. Our results suggest that in the domain of eating, and more generally, more attention should be paid to ecological factors, even though their mechanism of operation is transparent, and hence less revealing of fundamental psychological processes. Ironically, although the French eat less than Americans, they seem to eat for a longer period of time, and hence have more food experience. The French can have their cake and eat it as well.

Leu-574 of HIF-1alpha is essential for the von Hippel-Lindau (VHL)-mediated degradation pathway.

Oxygen homeostasis is crucial for a myriad of developmental, physiological, and pathophysiological processes. Hypoxia-inducible factor 1alpha (HIF-1alpha) plays a pivotal role in response to hypoxia by transcriptionally activating target genes involving oxygen uptake, transport, delivery, and consumption. HIF-1alpha activity is regulated primarily through the ubiquitin-proteasome degradation pathway, which targets the oxygen-dependent degradation domain (ODD) of HIF-1alpha. In particular, the von Hippel-Lindau (VHL) protein complex, an E3 ubiquitin ligase, binds to the ODD upon hydroxylation of HIF-1alpha Pro-564. Here, we show that in vivo VHL interacts with the N-terminal as well as the C-terminal ODD independently, supporting the notion of functional redundancy within the ODD. Moreover, we demonstrate that Leu-574 of HIF-1alpha is essential for VHL binding to the C-terminal ODD. Despite the presence of Pro-564, deletion or mutation of Leu-574 resulted in a loss of VHL binding and a gain of protein stability. Furthermore, the identification of Leu-574 redefines the N-terminal activation domain of HIF-1alpha to be constitutively active. Taken together, this study provides new insight into the mechanisms underlying VHL-mediated HIF-1alpha degradation and transcriptional activation, and a molecular basis for drug targeting.