Adaptation to low oxygen tension (hypoxia) in cells and tissues leads to the transcriptional induction of a series of genes that participate in angiogenesis, iron metabolism, glucose metabolism, and cell proliferation/survival. The primary factor mediating this response is the hypoxia-inducible factor-1 (HIF-1), an oxygen-sensitive transcriptional activator. HIF-1 consists of a constitutively expressed subunit HIF-1␤ and an oxygen-regulated subunit HIF-1␣ (or its paralogs HIF-2␣ and HIF-3␣). The stability and activity of the ␣ subunit of HIF are regulated by its post-translational modifications such as hydroxylation, ubiquitination, acetylation, and phosphorylation. In normoxia, hydroxylation of two proline residues and acetylation of a lysine residue at the oxygen-dependent degradation domain (ODDD) of HIF-1␣ trigger its association with pVHL E3 ligase complex, leading to HIF-1␣ degradation via ubiquitin-proteasome pathway. In hypoxia, the HIF-1␣ subunit becomes stable and interacts with coactivators such as cAMP response element-binding protein binding protein/p300 and regulates the expression of target genes. Overexpression of HIF-1 has been found in various cancers, and targeting HIF-1 could represent a novel approach to cancer therapy.The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key regulator responsible for the induction of genes that facilitate adaptation and survival of cells and the whole organism from normoxia (ϳ21% O 2 ) to hypoxia (ϳ1% O 2 ) (Wang et al., 1995;Semenza, 1998). Since the identification of HIF, 2 decades ago, our knowledge of it has grown exponentially. Because of the realization that hypoxia has a strong impact, via gene expression, on cell biology and mammalian physiology, there has been enormous growing interest in the biology of the HIF-1 pathway and its role in human diseases such as cancer. Therefore, this review considers what has been learned about HIF-1: its discovery, its regulation, its target gene, its role in development and disease, and its implication for therapy. The Discovery of HIF-1HIF-1␣. HIF-1 was discovered by the identification of a hypoxia response element (HRE; 5Ј-RCGTG-3Ј) in the 3Ј enhancer of the gene for erythropoietin (EPO), a hormone that stimulates erythrocyte proliferation and undergoes hypoxiainduced transcription (Goldberg et al., 1988;Semenza et al., 1991). Subsequent studies have revealed the protein that binds to the HRE under hypoxic conditions as HIF-1, a heterodimeric complex consisting of a hypoxically inducible subunit HIF-1␣ and a constitutively expressed subunit HIF-1␤ (Wang et al., 1995). HIF-1␤ is also known as the aryl hydrocarbon nuclear translocator (ARNT), which was originally identified as a binding partner of the aryl hydrocarbon receptor (Reyes et al., 1992), whereas HIF-1␣ was newly discovered. These proteins belong to the basic helix-loop-helixPer-ARNT-Sim (bHLH-PAS) protein family ( Fig. 1) (Wang et al., 1995). The bHLH and PAS motifs are required for heterodimer formation between the HIF-1␣ and HIF-1␤ ...

Chromium is a human carcinogen primarily by inhalation exposure in occupational settings. Although lung cancer has been established as a consequence of hexavalent chromium exposure in smokers and nonsmokers, some cancers of other tissues of the gastrointestinal and central nervous systems have also been noted. Except for a few reports from China, little is known about the health risks of environmental exposures to chromium. Likewise, there has been a lack of epidemiological studies of human exposure to hexavalent Cr by drinking water or ingestion, and it has been suggested that humans can perhaps tolerate hexavalent Cr at higher levels than the current drinking water standard of 50 ppb. This review highlights the most recent data on the induction of skin tumors in mice by chronic drinking-water exposure to hexavalent chromium in combination with solar ultraviolet light. This experimental system represents an important new animal model for chromate-induced cancers by ingestion of drinking water, and it suggests by extrapolation that chromate can likely be considered a human carcinogen by ingestion as well. The potential use of this animal model for future risk assessment is discussed.

The toxicity and carcinogenicity of hexavalent chromium (Cr) in animal and human models are reviewed. The focus of this review is not on the well-established fact that hexavalent Cr compounds of low and high water solubility can induce respiratory cancers, but rather this review addresses other types of cancers induced by exposure to hexavalent Cr compounds. Additionally, non-cancer endpoints are also discussed with documentation of human and animal studies showing non-cancer health effects of hexavalent Cr exposure on the respiratory system, GI system, immune system, liver, and kidney. There is an emerging understanding that because hexavalent chromate is isostructural with phosphate and sulfate, it is readily taken up by the G.I. tract and penetrates to many tissues and organs throughout the body. This is supported by animal studies and experiments using human volunteers. From the epidemiological studies, there is suggestive evidence that hexavalent Cr causes increased risk of bone, prostate, lymphomas, Hodgkins, leukemia, stomach, genital, renal, and bladder cancer, reflecting the ability of hexavalent chromate to penetrate all tissues in the body. A high accumulation of Cr(III) in all tissues and organs is a strong indication of the wide toxic potential of exposure to soluble hexavalent Cr in the drinking water and in the ambient environment.

Chromium, like many transition metal elements, is essential to life at low concentrations yet toxic to many systems at higher concentrations. In addition to the overt symptoms of acute chromium toxicity, delayed manifestations of chromium exposure become apparent by subsequent increases in the incidence of various human cancers. Chromium is widely used in numerous industrial processes, and as a result is a contaminant of many environmental systems. Chromium, in its myriad chemical forms and oxidation states, has been well studied in terms of its general chemistry and its interactions with biological molecules. However, the precise mechanisms by which chromium is both an essential metal and a carcinogen are not yet fully clear. The following review does not seek to embellish upon the proposed mechanisms of the toxic and carcinogenic actions of chromium, but rather provides a comprehensive review of these theories. The chemical nature of chromium compounds and how these properties impact upon the interactions of chromium with cellular and genetic targets, including animal and human hosts, are discussed.