Tumor development is characterized by an initial phase of rapid expansion, followed by a period of slowed growth as the proliferating malignant cells outstrip the local supply of oxygen and nutrients. In the absence of a dedicated blood supply, early-stage tumors attain steady-state volumes of only a few cubic millimeters, at which time the rate of cell death, due to oxygen and nutrient depletion, equals the rate of cell division (19). To resume growth, these microtumors must adapt to hypoxic stress through alterations in cellular metabolism and the stimulation of neovascularization, which provides the additional blood needed to sustain cellular proliferation. Accordingly, cellular adaptation to growth during hypoxic stress contributes to malignant progression and is correlated with a poor clinical outcome in several types of cancer (3, 4, 18). Two hallmark features of hypoxic adaptation are increased rates of anaerobic glycolysis and the secretion of proangiogenic factors, such as vascular endothelial growth factors (VEGFs) (28, 39). The molecular mechanisms that underlie cellular responses to hypoxic stress are therefore of considerable relevance to cancer biology and therapy.A key regulator of the cellular response to oxygen deprivation is the transcription factor, hypoxia-inducible factor 1 (HIF-1). Originally identified as an oxygen-responsive activator of erythropoietin gene transcription, HIF-1 is now known to play a central role in the maintenance of oxygen homeostasis in virtually all bodily tissues (42, 43). The predominant form of HIF-1 is a heterodimer consisting of HIF-1␣ and HIF-1 subunits, both of which are members of the basic helix-loop-helix family of transcription factors. Although HIF-1 is a constitutively expressed nuclear protein, the expression of the HIF-1␣ subunit is tightly coupled to the ambient oxygen tension. Under normoxic conditions, the HIF-1␣ gene is continuously transcribed and translated; however, the HIF-1␣ protein is expressed at very low levels due to rapid destruction via the ubiquitin-proteasome pathway. In addition to its DNA-binding and transactivating motifs, HIF-1␣ contains a stretch of ca. 200 amino acids, termed the oxygen-dependent degradation (ODD) domain. As its name implies, the ODD domain mediates the interaction between HIF-1␣ and the E3 ubiquitin ligase complex that mediates continuous poly ubiquitination of HIF-1␣ in normoxic cells.The oxygen-dependent turnover of HIF-1␣ is governed by a novel family of prolyl 4-hydroxylases (PHDs) that specifically modify HIF-1␣ at two conserved proline residues (Pro-402 and Pro-564), both located in the ODD domain (5,15,27,41). Prolyl hydroxylation triggers the recognition of HIF-1␣ by the product of the VHL tumor suppressor gene, which serves as the targeting subunit of an E3 ubiquitin ligase complex (20). Although the exact mechanism remains unclear, a decrease in ambient oxygen tension leads to a correlative decrease in HIF-1␣ prolyl hydroxylation, which in turn leads to decreased rates of HIF-1␣ polyubiquitination and...
The immunosuppressant rapamycin interferes with G1-phase progression in lymphoid and other cell types by inhibiting the function of the mammalian target of rapamycin (mTOR). mTOR was determined to be a terminal kinase in a signaling pathway that couples mitogenic stimulation to the phosphorylation of the eukaryotic initiation factor (eIF)-4E-binding protein, PHAS-I. The rapamycin-sensitive protein kinase activity of mTOR was required for phosphorylation of PHAS-I in insulin-stimulated human embryonic kidney cells. mTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E. These studies define a role for mTOR in translational control and offer further insights into the mechanism whereby rapamycin inhibits G1-phase progression in mammalian cells.
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