Cytotoxic signaling by inhibitors of DNA topoisomerase II

Abstract

Apoptosis is coordinated by a family of cysteine proteases, the caspases, that dismantle the cell by targeting a panoply of proteins for limited proteolysis. The mammalian caspase family contains 14 members, a subset of which participate in apoptosis, with the remainder likely to be involved in the processing of pro-inflammatory cytokines. Our current research is focused upon establishing the repertoire and order of caspase activation events that occur during the signalling and demolition phases of apoptosis. Apical caspase activation events are typically initiated by adaptor molecules that promote caspase aggregation and facilitate caspase autoactivation. In contrast, distal caspase activation events are controlled by caspases activated earlier in the cascade. Many cellular stresses provoke apoptosis by damaging mitochondria which results in the release of factors (such as cytochrome c and Smac/Diablo) that trigger caspase activation and cell death as a consequence. Here, we discuss the hierarchical nature of the caspase cascade that is triggered upon release of mitochondrial cytochrome c into the cytoplasm and the role of specific caspases within this cascade in targeting proteins for degradation. Finally, feedback amplification loops and important control points within the caspase cascade will also be discussed.

Efek Ekstrak Etanol Daun Kemangi (Ocimum sanctum L.) Sebagai Agen Kemopreventif Pada Sel Kanker Leher Rahim Hela Melalui Aktivitas Sitotoksik Dan Induksi Apoptosis

“…Topoisomerase I memotong satu rantai sedangkan topoisomerase II memotong kedua rantai. Inhibitor topoisomerase menstabilkan kompleks topoisomerase-DNA terpotong, sehingga menghasilkan kerusakan DNA double stranded yang permanen (Beck et al, 2001). Hal ini akan menyebabkan kerusakan DNA, sehingga menginduksi ekspresi p53 dan meng-upregulasi protein p53-dependent (seperti Bax, p21, Gadd45) yang merupakan tahap awal terjadinya apoptosis.…”