Mitochondrial cytochrome b sequence variation and phylogenetics of the highly specialized schizothoracine fishes (Teleostei : Cyprinidae) in the Qinghai-Tibet Plateau

The complete 1140 bp mitochondial cytochrome b sequences were obtained from 39 individuals representing five species of all four genera of highly specialized schizothoracine fishes distributed in the Qinghai-Tibet plateau. Sequence variation of the cytochrome b gene was surveyed among the 39 individuals as well as three primitive schizothoracines and one outgroup. Phylogenetic analysis suggested that the group assignment based on 1140 bp of the cytochrome b sequence is obviously; different from previous assignments, and the highly specialized schizothoracine fishes (Schizopygopsis pylzovi, Gymnocypris przewalskii, G. eckloni, Chuanchia lablosa, and Platypharodon extremus) form a monophyletic group that is sister to the clade formed by the primitive schizothoracine fishes (Schizothorax prenanti, S. pseudaksaiensis, and S. argentatus). The haplotypes of Schizopygopsis pylzovi and G. przewalskii were paraphyletic based on cytochrome b data, which most likely reflected incomplete sorting of mitochondrial DNA lineages. The diploid chromosome numbers of Schizofhoracinae were considered in phylogenetic analysis and provided a clear pattern of relationships. Molecular dating estimated for highly specialized schizothoracine fishes suggested that the highly specialized schizothoracine fishes diverged in the late Miocene Pliocene to Pleistocene (4.5x10(4)-4.05x10(6) Years BP). The relationship between the cladogenesis of highly specialized schizothoracine fishes and geographical events of the Qinghai-Tibet plateau is discussed.

Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues.

Brain tumors are typically resistant to conventional chemotherapeutics, most of which initiate apoptosis upstream of mitochondrial cytochrome c release. In this study, we demonstrate that directly activating apoptosis downstream of the mitochondria, with cytosolic cytochrome c, kills brain tumor cells but not normal brain tissue. Specifically, cytosolic cytochrome c is sufficient to induce apoptosis in glioblastoma and medulloblastoma cell lines. In contrast, primary neurons from the cerebellum and cortex are remarkably resistant to cytosolic cytochrome c. Importantly, tumor tissue from mouse models of both high-grade astrocytoma and medulloblastoma display hypersensitivity to cytochrome c when compared with surrounding brain tissue. This differential sensitivity to cytochrome c is attributed to high Apaf-1 levels in the tumor tissue compared with low Apaf-1 levels in the adjacent brain tissue. These differences in Apaf-1 abundance correlate with differences in the levels of E2F1, a previously identified activator of Apaf-1 transcription. ChIP assays reveal that E2F1 binds the Apaf-1 promoter specifically in tumor tissue, suggesting that E2F1 contributes to the expression of Apaf-1 in brain tumors. Together, these results demonstrate an unexpected sensitivity of brain tumors to postmitochondrial induction of apoptosis. Moreover, they raise the possibility that this phenomenon could be exploited therapeutically to selectively kill brain cancer cells while sparing the surrounding brain parenchyma.