404 AMPK Positively Regulates Neurotensin Secretion Through Inhibition of mTORC1 Signaling

Abstract

from SurviviniΔIEC and control mice. Survivin deletion was performed by addition of tamoxifen. Specimens were investigated by quantitative PCR, immunohistochemistry and western blot analysis. Results: Time course analysis of gene deletion of survivin in IECs revealed an initial pulse of apoptosis at the crypt bottom 48 hours after tamoxifen injection. This did not led to death of SurviviniΔIEC animals. Histological analysis at later time points revealed aberrant chromosome segregation in IECs and the formation of multinucleated cells starting from the crypt bottom. Importantly, these cells did not show signs of cell death but of DNA damage, as confirmed by phopho-H2AX and phospho-p53 positive nuclei. Quantitative PCR showed elevated gene expression levels of p21 and ddit3 (dna-damageinducible-transcript 3) in SurviviniΔIEC mice, suggesting mitotic catastrophe in IEC depleted of survivin. Conclusions: Although survivin belongs to the IAP family, we could not see extensive apoptosis after survivin deletion in IECs. Our data demonstrates that the loss of survivin initially leads to the death of apoptosis prone IECs, followed by the formation of multinucleated cells with signs of DNA damage in apoptosis reluctant IECs. This leads to an alternative cell death pathway, known as mitotic catastrophe.