Non-apoptotic function of caspases in a cellular model of hydrogen peroxide-associated colitis.
Bottom Line: Conversely, we found that oxidative stress led to caspase-dependent proteolytic degradation of the DNA-damage checkpoint protein ATM that is upstream of γ-H2AX.As a consequence, undetected DNA-damage and increased proliferation were found in repeatedly H2 O2 -exposed HCEC.Such features have been associated with neoplastic transformation and appear here to be mediated by a non-apoptotic function of caspases.
Affiliation: Department of Pathology, Otto-von-Guericke University, Magdeburg, Germany. email@example.comShow MeSH
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Mentions: Cell cycle analysis following caspase inhibition using Z-VAD-FMK showed (i) fewer cells in S- and more cells in the G1-phase after 24 hrs, (ii) fewer cells in G2/M- and more cells in the S-, G1-phase and debris after 48 hrs and (iii) fewer cells in G2/M-phase, but more cell debris after 72 hrs (Fig. 3A, G1: 14.5–21.6% after 24 hrs, 10.2–16.3% after 48 hrs; cell debris: 58.0–67.0% after 72 hrs). Thus, caspases seem to promote progression of cells through the G1- and S-phase by overriding the G1/S- and intra-S checkpoint, respectively. Consequently, caspases support cell survival by halting cells in the G2/M-phase after 72 hrs. Without proteolytic active caspases, a considerably higher percentage of cells underwent apoptosis (Fig. 3A, cell debris: 67.0% instead of 58.0%). It is apparent, therefore, that apoptosis is caspase-independent and that survival is dependent on proteolytic active caspases, generating cleaved caspase fragments (Fig. 2A).
Affiliation: Department of Pathology, Otto-von-Guericke University, Magdeburg, Germany. firstname.lastname@example.org