The p53-Mdm2 feedback loop is perceived to be critical for regulating stress-induced p53 activity and levels. However, this has never been tested in vivo. Using a genetically engineered mouse with mutated p53 response elements in the Mdm2 P2 promoter, we show that feedback loop-deficient Mdm2 P2/P2 mice are viable and aphenotypic and age normally. p53 degradation kinetics after DNA damage in radiosensitive tissues remains similar to wild-type controls. Nonetheless, DNA damage response is elevated in Mdm2 P2/P2 mice. Enhanced p53-dependent apoptosis sensitizes hematopoietic stem cells (HSCs), causing drastic myeloablation and lethality. These results suggest that while basal Mdm2 levels are sufficient to regulate p53 in most tissues under homeostatic conditions, the p53-Mdm2 feedback loop is critical for regulating p53 activity and sustaining HSC function after DNA damage. Therefore, transient disruption of p53-Mdm2 interaction could be explored as a potential adjuvant/therapeutic strategy for targeting stem cells in hematological malignancies.
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Balloon-tipped catheters were used to occlude the external carotid artery and its branches in nine horses with hemorrhage caused by guttural pouch mycosis. The internal carotid artery on the affected side was occluded simultaneously in four horses and had been occluded previously in two others. In three horses, a single balloon-tipped catheter was inserted in the external carotid artery beneath the floor of the guttural pouch and its tip was advanced blindly into distal branches. In one horse, the superficial temporal artery was occluded briefly during surgery by a balloon-tipped catheter so a catheter inserted into the external carotid artery could be diverted into the maxillary artery. In the other five horses, the external carotid artery was occluded proximally and the maxillary artery was occluded immediately caudal to the alar canal by a balloon-tipped catheter inserted into the major palatine artery. Serious postoperative hemorrhage did not occur in eight horses, but one horse that had a single balloon-tipped catheter inserted into the external carotid artery had profuse hemorrhage 11 days after surgery and was euthanatized. One horse was euthanatized because of persistent dysphagia. The only complication related to use of balloon catheters was a mild incisional infection in one horse. It was concluded that the external carotid and maxillary arteries must be occluded on both sides of the eroded segment to prevent hemorrhage from normograde and retrograde flow.
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