Hypoxia induces differential translation of enolase/MBP-1

Abstract

BackgroundHypoxic microenvironments in tumors contribute to transformation, which may alter metabolism, growth, and therapeutic responsiveness. The α-enolase gene encodes both a glycolytic enzyme (α-enolase) and a DNA-binding tumor suppressor protein, c-myc binding protein (MBP-1). These divergent α-enolase gene products play central roles in glucose metabolism and growth regulation and their differential regulation may be critical for tumor adaptation to hypoxia. We have previously shown that MBP-1 and its binding to the c-myc P2 promoter regulates the metabolic and cellular growth changes that occur in response to altered exogenous glucose concentrations.ResultsTo examine the regulation of α-enolase and MBP-1 by a hypoxic microenvironment in breast cancer, MCF-7 cells were grown in low, physiologic, or high glucose under 1% oxygen. Our results demonstrate that adaptation to hypoxia involves attenuation of MBP-1 translation and loss of MBP-1-mediated regulation of c-myc transcription, evidenced by decreased MBP-1 binding to the c-myc P2 promoter. This allows for a robust increase in c-myc expression, "early c-myc response", which stimulates aerobic glycolysis resulting in tumor acclimation to oxidative stress. Increased α-enolase mRNA and preferential translation/post-translational modification may also allow for acclimatization to low oxygen, particularly under low glucose concentrations.ConclusionsThese results demonstrate that malignant cells adapt to hypoxia by modulating α-enolase/MBP-1 levels and suggest a mechanism for tumor cell induction of the hyperglycolytic state. This important "feedback" mechanism may help transformed cells to escape the apoptotic cascade, allowing for survival during limited glucose and oxygen availability.

Genomic c-Myc Quadruplex DNA Selectively Kills Leukemia

“…RNA purity was determined by A260/A280 ratio and quantified by A260. Preparation of cDNA and forward and reverse primers for c-myc and β- actin were as previously described (18). RT-PCR was performed for a uniform amount of cDNA using the Fast 7500 System (Applied Biosystems).…”

“…ROS generation was assessed as previously described (18) by 2′, 7′-dichlorofluorescin diacetate (DCFH-DA) (Sigma Chemical), a lipid– permeable non-fluorescent compound that when oxidized by intracellular reactive oxygen species (ROS), forms the fluorescent compound 2′, 7′-dichlorofluorescein (DCF). U937 cells were plated in phenol-red free RPMI containing 10μM DCFH-DA and treated with PU27 or MutPU27.…”

Circulating CD34+ progenitor cell frequency is associated with clinical and genetic factors

“…ENO1 codes for ␣-enolase and c-myc binding protein (MBP-1), which are involved in glucose metabolism and cellular growth regulation. 42 Modulation of ENO1-encoded proteins is implicated in cellular survival in the setting of hypoxia, suggesting that the ENO1 locus could influence the viability of CD34 ϩ cell development in the relatively hypoxic environment of the BM. RERE is notable for interactions with genes involved in hematopoiesis.…”

Skeletal muscle proteome and meat quality of broiler chickens subjected to gas stunning prior slaughter or slaughtered without stunning

“…Beta-enolase is abundant in striated muscles particularly during the growth and developmental phase (Doherty et al, 2004). In a study on tumor cells, Sedoris, Thomas, and Miller (2010) found increased expression of enolase protein in response to hypoxia (deprivation of oxygen supply). The authors also found that the increased enolase expression was influenced by differences in glucose levels.…”