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They are different from heat-shock response elements, which are also often abbreviated as HRE; there are only so many three-letter acronyms...

cells. This growth factor stimulates the proliferation and maturation of erythroid precursors in the bone marrow leading to 'polycythemia'. Erythropoetin production is regulated by the kidney in response to changes in oxygen partial pressure, e.g., at high altitudes. Constitutive activation of the hypoxia response in renal tumor cells can therefore lead to increased erythropoesis, which is one of several 'paraneoplastic' symptoms found in renal carcinoma patients. Such symptoms can be confounding in diagnosis, because they suggest completely different diseases.

Glucose and lipid metabolism: HIF transcription factors change the metabolism of glucose and of lipids. Target genes in this regard include the glucose transporter GLUT1 and many glycolytic enzymes, such as LDH, aldolase, and PGK. For many glycolytic enzymes, several isoenzymes are expressed in a tissue-specific fashion, depending whether the tissue performs glycolysis or gluconeogenesis. Hypoxia invariably induces the glycolytic over the gluconeogenic isoenzyme. The kidney, particularly in its proximal tubules, is capable of gluconeogenesis, like the liver and the intestine. Therefore, in VHL clear-cell carcinoma proximal tubule cells switch from gluconeogenesis to glycolysis as well as to glycogen and lipid storage. Much of this metabolic switch, like increased angiogenesis, can be accounted for by constitutive HIF activation.

Growth factors: In addition to VEGF, active HIFs induce further growth factors acting in a paracrine fashion, e.g. on endothelial cells, as well as in an autocrine fashion on the producing cell itself. These include PDGF, TGFp factors, and -perhaps most significant in renal epithelial cells - TGFa, an important ligand of the EGFR. Within the cell, the PI3K pathway (^6.3) may be activated, independent of growth factor signals.

Apoptosis: While hypoxia elicites potential growth signals, it also promotes apoptosis. The fate of a hypoxic cell may therefore be decided by the relative balance of these signals. TP53 is activated and would be expected to not only promote apoptosis via BAX upregulation, but also to antagonize the pro-angiogenic response (^6.6). The proapoptotic NIX and NIP3 proteins (Table 7.1) may constitute specific mediators of hypoxia-induced apoptosis.

Regulation of pH: The carbonic anhydrases CA9 and CA12 are among the most strongly HIF 1-inducible proteins. These proteins are mainly located at the cell membrane and regulate pH by accelerating the reaction between CO2 and H2O (in both directions). In a hypoxic environment, they favor the establishment of a low pH through the dissociation of carbonic acid.

Table 15.5. A selection of proteins induced by HIFs

Function

Examples

Oxygen supply and angiogenesis

Glucose metabolism

Growth factors and growth factor signaling DNA repair and cell protection

Apoptosis pH regulation Cell adhesion and extracellular matrix remodeling

ETI (endothelin-1), ET2, iNOS, COX2, heme oxygenase, ferritin, transferrin, transferrin receptor, VEGF, PDGF, ANG-2, VEGFR1, TIE1 (angiopoetin receptor), IL8, PAI1, erythropoetin

LDH, pyruvate kinase, PGK, GAPDH, aldolase, PFK (glycolytic isoenzymes), hexokinase, GLUT1, GLUT3

TGFa, TGFß, HGF, PDGF, FGF3, VEGFA, EGFR, PI3K activity, IL6, IL8, p27KIP1, p21CIP1 HSF (heat-shock factor), HIF1a, HIF2a, GADD153, HAP1 (AP-endonuclease), thioredoxin, KU70, KU80 NIX, NIP3, PI3K activity, IGFBP3, NFKB, spermidine acetyltransferase Carbonic anhydrases IX and XII (CA9, CA12) Specific collagens, metalloproteinases, specific CAMs (cell adhesion molecules), proline 4-hydroxylase, uPAR, vimentin, specific integrins

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