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Stress elicits adrenal epinephrine and cortisol release into the bloodstream to initiate physiological and behavioral responses to counter and overcome stress, the classic 'fight or flight' response (Cannon and De La Paz, Am J Physiol 28:64-70, ). Stress and the stress hormone epinephrine also contribute to the pathophysiology of illness, e.g., behavioral disorders, cardiovascular disease, and immune dysfunction. Epinephrine itself is regulated by stress through its biosynthesis by phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28). Single and repeated immobilization (IMMO) stress in rats stimulates adrenal PNMT mRNA and protein expression via the transcription factors, Egr-1 and Sp1. Moderate hypoxic stress increases PNMT promoter-driven gene expression and endogenous PNMT mRNA and protein in PC12 cells. Induction is initiated through cAMP and PLC signaling, with PKA, PKC, PI3K, ERK1/2 MAPK, and p38 MAPK continuing downstream signal transduction, followed by activation of HIF1α, Egr-1, and Sp1. While functional Egr-1 and Sp1 binding sites exist within the proximal PNMT promoter, a putative hypoxia response element is a weak HIF binding site. Yet, HIF1α overexpression increases PNMT promoter-driven luciferase activity and endogenous PNMT. When the Egr-1 or Sp1 sites are mutated, HIF1α does not stimulate the PNMT promoter. siRNA knock down of Egr-1 or Sp1 prevents promoter activation while siRNA knock down of HIF1α inhibits Egr-1 and Sp1 induction. Findings suggest that hypoxia activates the PNMT gene indirectly via HIF1α stimulation of Egr-1 and Sp1. Thus, for stress-induced illnesses where adrenergic dysfunction is implicated, HIF1α may be an 'on-off' switch regulating adrenergic responses to stress and a potential target for therapeutic intervention. [ABSTRACT FROM AUTHOR]