The naturally occurring human cytochrome c variant (G41S) is associated with a mild autosomal dominant thrombocytopenia (Thrombocytopenia Cargeeg) caused by dysregulation of platelet production. The molecular basis of the platelet production defect is unknown. Despite high conservation of cytochrome c between human and mouse (91.4% identity), introducing the G41S mutation into mouse cytochrome ...

Although apoptosis has been extensively studied in developing neurons, the dynamic changes in this pathway after neuronal maturation remain largely unexplored. We show that as neurons mature, cytochrome c- mediated apoptosis progresses from inhibitor of apoptosis protein-dependent to -independent regulation because of a complete loss of Apaf-1 expression. However, after DNA damage, mature neuro...

poptosis after growth factor withdrawal or drug treatment is associated with mitochondrial cytochrome c release and activation of Apaf-1 and caspase-9. To determine whether loss of Apaf-1, caspase-2, and caspase-9 prevented death of factor-starved cells, allowing them to proliferate when growth factor was returned, we generated IL-3–dependent myeloid lines from gene-deleted mice. Long after gro...

PURPOSE To investigate predictive value of APAF-1 and COX-2 expression in pathologic complete response (pCR) for patients with rectal adenocarcinoma (RAC) who were treated with neoadjuvant chemoradiotherapy (neo-CRT) followed by total mesorectal excision (TME).   MATERIALS AND METHODS Immunohistochemistry assay was used to detect expression of APAF-1 and COX-2 in paraffin-wax embedded tissues...

Apoptosis after growth factor withdrawal or drug treatment is associated with mitochondrial cytochrome c release and activation of Apaf-1 and caspase-9. To determine whether loss of Apaf-1, caspase-2, and caspase-9 prevented death of factor-starved cells, allowing them to proliferate when growth factor was returned, we generated IL-3-dependent myeloid lines from gene-deleted mice. Long after gr...

Mutations in the gene coding for leucine-rich repeat kinase 2 (LRRK2) cause autosomal-dominant Parkinson's disease. The pathological mutations have been associated with an increase of LRRK2 kinase activity, although its physiological substrates have not been identified yet. The data we report here demonstrate that disease-associated mutant LRRK2 cell toxicity is due to mitochondria-dependent ap...

Cytochrome c (CC)-initiated Apaf-1 apoptosome formation represents a key initiating event in apoptosis. This process can be reconstituted in vitro with the addition of CC and ATP or dATP to cell lysates. How physiological levels of nucleotides, normally at high mM concentrations, affect apoptosome activation remains unclear. Here we show that physiological levels of nucleotides inhibit the CC-i...

PURPOSE Apoptotic protease-activating factor-1 (APAF-1) and cathepsin B are important functional proteins in apoptosis; the former is involved in the intrinsic (mitochondrial) pathway, while the latter is associated with both intrinsic and extrinsic pathways. Changes in the expression of apoptosome-related proteins could be useful indicators of tumor development since a priori defects in the mi...

How Bcl-2 and its pro-survival relatives prevent activation of the caspases that mediate apoptosis is unknown, but they appear to act through the caspase activator apoptosis protease–activating factor 1 (Apaf1). According to the apoptosome model, the Bcl-2–like proteins preclude Apaf-1 activity by sequestering the protein. To explore Apaf-1 function and to test this model, we generated monoclon...