Regulation of hypoxia-inducible factor-1α, regulated in development and DNA damage response-1 and mammalian target of rapamycin in human placental BeWo cells under hypoxia

Placenta ◽  
2016 ◽  
Vol 45 ◽  
pp. 24-31 ◽  
Author(s):  
F. Zhou ◽  
L.B. Guan ◽  
P. Yu ◽  
X.D. Wang ◽  
Y.Y. Hu
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Target Of Rapamycin ◽  
Hypoxia Inducible Factor 1Α ◽  
Bewo Cells ◽  
Damage Response

scholarly journals ATM Activation and Signaling under Hypoxic Conditions

2008 ◽  
Vol 29 (2) ◽  
pp. 526-537 ◽  
Author(s):  
Zuzana Bencokova ◽  
Muriel R. Kaufmann ◽  
Isabel M. Pires ◽  
Philip S. Lecane ◽  
Amato J. Giaccia ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Hypoxia Inducible Factor ◽  
Dna Breaks ◽  
Focus Formation ◽  
Atm Kinase ◽  
Mrn Complex ◽  
Hypoxic Conditions ◽  
Damage Response ◽  
Dependent Cell

ABSTRACT The ATM kinase has previously been shown to respond to the DNA damage induced by reoxygenation following hypoxia by initiating a Chk 2-dependent cell cycle arrest in the G2 phase. Here we show that ATM is both phosphorylated and active during exposure to hypoxia in the absence of DNA damage, detectable by either comet assay or 53BP1 focus formation. Hypoxia-induced activation of ATM correlates with oxygen concentrations low enough to cause a replication arrest and is entirely independent of hypoxia-inducible factor 1 status. In contrast to damage-activated ATM, hypoxia-activated ATM does not form nuclear foci but is instead diffuse throughout the nucleus. The hypoxia-induced activity of both ATM and the related kinase ATR is independent of NBS1 and MRE11, indicating that the MRN complex does not mediate the DNA damage response to hypoxia. However, the mediator MDC1 is required for efficient activation of Kap1 by hypoxia-induced ATM, indicating that similarly to the DNA damage response, there is a requirement for MDC1 to amplify the ATM response to hypoxia. However, under hypoxic conditions, MDC1 does not recruit BRCA1/53BP1 or RNF8 activity. Our findings clearly demonstrate that there are alternate mechanisms for activating ATM that are both stress-specific and independent of the presence of DNA breaks.

scholarly journals Small-Molecule Activation of p53 Blocks Hypoxia-Inducible Factor 1α and Vascular Endothelial Growth Factor Expression In Vivo and Leads to Tumor Cell Apoptosis in Normoxia and Hypoxia

2009 ◽  
Vol 29 (8) ◽  
pp. 2243-2253 ◽  
Author(s):  
Jun Yang ◽  
Afshan Ahmed ◽  
Evon Poon ◽  
Nina Perusinghe ◽  
Alexis de Haven Brandon ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Cell ◽  
Dna Damage Response ◽  
Cell Apoptosis ◽  
Hypoxia Inducible Factor ◽  
Vascular Endothelial ◽  
Tumor Cell Apoptosis ◽  
Damage Response ◽  
Endothelial Growth Factor

ABSTRACT The p53 tumor suppressor protein negatively regulates hypoxia-inducible factor 1α (HIF-1α). Here, we show that induction of p53 by the small-molecule RITA (reactivation of p53 and induction of tumor cell apoptosis) [2,5-bis(5-hydroxymethyl-2-thienyl) furan] (NSC-652287) inhibits HIF-1α and vascular endothelial growth factor expression in vivo and induces significant tumor cell apoptosis in normoxia and hypoxia in p53-positive cells. RITA has been proposed to stabilize p53 by inhibiting the p53-HDM2 interaction. However, induction of p53 alone was insufficient to block HIF-1α induced in hypoxia and has previously been shown to require additional stimuli, such as DNA damage. Here, we identify a new mechanism of action for RITA: RITA activates a DNA damage response, resulting in phosphorylation of p53 and γH2AX in vivo. Unlike other DNA damage response-inducing agents, RITA treatment of cells induced a p53-dependent increase in phosphorylation of the α subunit of eukaryotic initiation factor 2, requiring PKR-like endoplasmic reticulum kinase activity, and led to the subsequent downregulation of HIF-1α and p53 target proteins, including HDM2 and p21. Through the identification of a new mechanism of action for RITA, our study uncovers a novel link between the DNA damage response-p53 pathway and the protein translational machinery.

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