Nzyme transcription and secretion while not being involved in CreA derepression. This supports the hypothesis that other pathways for SnfA and SchA induction exist. Autophagy is a highly conserved process in eukaryotic cells and occurs in response to a diverse array of conditions, including nutrient deprivation (Martinet et al. 2006; Mizushima and Klionsky 2007). Carbon-starved A. nidulans downregulated mitochondrial functions and aerobic respiration while upregulating autophagy, vesicle transport, and protein targeting to the vacuole. A dramatic reduction in autophagy was observed in the atmA strain, strongly suggesting that AtmA positively regulates autophagy. Autophagy forms part of a starvation-induced prosurvival strategy, which is inhibited by the action of TOR, PKA, and Sch9 on the Atg1 kinase in S. cerevisiae (Kamada et al. 2000; Yorimitsu et al. 2007). In A. nidulans, AtgAATG1 was confirmed to be essential for the induction of autophagy, whereas the absence of AtmA resulted in the loss of AtgHATG8 vacuole localization and impaired autophagy. Therefore, the reduction in autophagy in the atmA strain could have contributed to the faster rate of starvation-induced cell death.Volume 4 January 2014 |ATM Kinase and Carbon Starvation Response |Figure 9 Detection of necrosis using propidium iodide (PI) staining for wild-type, atmA, and xprG strains after 0, 12, and 24 hr of starvation. Nuclei were visualized by Hoescht staining. (A) Wild-type, (B) DatmA, and (C) DxprG. Bars: 10 mm.In mammalian cells, p53 is a multi-functional protein that simultaneously regulates distinct downstream pathways controlling antioxidant defense, cell-cycle progression, mitochondrial respiration, glucose homeostasis, and apoptosis (Ko and Prives 1996; Levine 1997; Armata et al. 2010). Different residues of the p53 protein are phosphorylated by ATM on exposure to distinct stimuli (Bensimon et al. 2011; Ditch and Paull 2012). In response to DNA damage and during the regulation of glucose homeostasis, ATM phosphorylates p53, resulting in its activation and an increase in protein stability (Shiloh 2006; Armata et al. 2010). In mammalian cells, p53-induced autophagy has been reported (Inoki et al. 2003; Zhao and Klionsky 2011). In A. nidulans, autolysis and starvation-induced protease secretion are controlled by the p53-like transcription factor XprG (Katz et al. 2006, 2009). The present study suggests that AtmA regulated the XprG-dependent starvation-induced protease secretion and cell death.ROS act as signaling molecules and cellular toxicants. Mitochondrial dysfunction or the impairment of oxidative phosphorylation results in ROS accumulation (Barros et al. 2004). A shift in the balance between oxidants/antioxidants in the direction of oxidation contributes to the induction of apoptosis (Liu et al.Bafilomycin A1 2008; Giorgio et al.PhIP 2007).PMID:24576999 In mammalian cells, p53 mediates antioxidant pathways and thereby protects against endogenous ROS. After stress, high levels of p53 lead to a shift in oxidant/antioxidant balance, which can result in apoptotic cell death (Kang et al. 2013). Atm-deficient mammalian cells demonstrate increased ROS levels and oxidative stress (Barlow et al. 1999; Gatei et al. 2001; Kamsler et al. 2001), with both conditions resulting in the phosphorylation of p53 at the ATM site (Armata et al. 2010). In A. nidulans, AtmA negatively regulated XprGdependent ROS accumulation. Therefore, the absence of AtmA or XprG would result in faster and slower rates in ROS-m.
