Regulation of cellular metabolism during proliferation and stress conditions

Mammalian cell growth and survival is regulated by the integration of signals from growth factors. These signals regulate metabolism allowing cells to meet its biosynthetic and energy needs. While proliferative signals activate anabolic metabolism in order to meet biosynthetic demands, cells activate catabolic metabolism in order to maintain energy demands under stress conditions. Apoptotic resistant Bax-/-Bak-/- cells were studied under proliferative and stressed conditions to further understand how such cells metabolically adapt to defined stresses. Bax -/-Bak-/- T lymphocytes display apoptosis resistance, but have impaired proliferation. The cells displayed defective respiration and reactive oxygen species (ROS) production, both of which are attributed to defects in endoplasmic reticulum calcium signaling. Although resting IL-3 dependent Bax-/-Bak-/- cells can survive hypoxia in the absence of hypoxia inducible factor 1-alpha (HIF-1alpha), proliferating cells neither increase nor depend on HIF-1alpha for continued cell survival. Growth factor signaling is necessary for the induction of HIF-1alpha under hypoxia. Growth factor-dependent HIF-1alpha expression reprogrammed the intracellular fate of glucose, resulting in decreased glucose-dependent anabolic synthesis and increased lactate production. Survival of cells in the absence of either growth factor or oxygen was found to be dependent of autophagy. Growth factor dependent suppression of autophagy during recovery from metabolic stress was found to be dependent on JAK-STAT signaling. JAK-STAT signaling activated anabolic metabolism independently of AKT-mTOR signaling. These studies address the interrelation between signal transduction, cellular metabolism, and stress stimuli.