An association between sex-specific fitness and gene expression in the fruit fly provides an estimate of number, identity and function of sexually antagonistic genes in this species.

Mitochondria are maternally transmitted; hence, their genome can only make a direct and adaptive response to selection through females, whereas males represent an evolutionary dead end. In theory, this creates a sex-specific selective sieve, enabling deleterious mutations to accumulate in mitochondrial genomes if they exert male-specific effects. We tested this hypothesis, expressing five mitochondrial variants alongside a standard nuclear genome in Drosophila melanogaster, and found striking sexual asymmetry in patterns of nuclear gene expression. Mitochondrial polymorphism had few effects on nuclear gene expression in females but major effects in males, modifying nearly 10% of transcripts. These were mostly male-biased in expression, with enrichment hotspots in the testes and accessory glands. Our results suggest an evolutionary mechanism that results in mitochondrial genomes harboring male-specific mutation loads.

The purpose of this study was to investigate the antiangiogenic and in vivo properties of the recently identified phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor Inositol(1,3,4,5,6) pentakisphosphate [Ins(1,3,4,5,6)P 5 ]. Because activation of the PI3K/Akt pathway is a crucial step in some of the events leading to angiogenesis, the effect of Ins(1,3,4,5,6)P 5 on basic fibroblast growth factor (FGF-2)-induced Akt phosphorylation, cell survival, motility, and tubulogenesis in vitro was tested in human umbilical vein endothelial cells (HUVEC). The effect of Ins(1,3,4,5,6)P 5 on FGF-2-induced angiogenesis in vivo was evaluated using s.c. implanted Matrigel in mice. In addition, the effect of Ins(1,3,4,5,6)P 5 on growth of ovarian carcinoma SKOV-3 xenograft was tested. Here, we show that FGF-2 induces Akt phosphorylation in HUVEC resulting in antiapoptotic effect in serum-deprived cells and increase in cellular motility. Ins(1,3,4,5,6)P 5 blocks FGF-2-mediated Akt phosphorylation and inhibits both survival and migration in HUVEC. Moreover, Ins(1,3,4,5,6)P 5 inhibits the FGF-2-mediated capillary tube formation of HUVEC plated on Matrigel and the FGF-2-induced angiogenic reaction in BALB/c mice. Finally, Ins(1,3,4,5,6)P 5 blocks the s.c. growth of SKOV-3 xenografted in nude mice to the same extent than cisplatin and it completely inhibits Akt phosphorylation in vivo. These data definitively identify the Akt inhibitor Ins(1,3,4,5,6)P 5 as a specific antiangiogenic and antitumor factor. Inappropriate activation of the PI3K/Akt pathway has been linked to the development of several diseases, including cancer, making this pathway an attractive target for therapeutic strategies. In this respect, Ins(1,3,4,5,6)P 5 , a water-soluble, natural compound with specific proapoptotic and antiangiogenic properties, might result in successful anticancer therapeutic strategies. (Cancer Res 2005; 65(18): 8339-49)

Phosphoinositide 3-kinase (PI 3-K) is implicated in a wide array of biological and pathophysiological responses, including tumorigenesis, invasion and metastasis, therefore specific inhibitors of the kinase may prove useful in cancer therapy. We propose that specific inositol polyphosphates have the potential to antagonize the activation of PI 3-K pathways by competing with the binding of PtdIns(3,4,5)P 3 to pleckstrin homology (PH) domains. Here we show that Ins(1,3,4,5,6)P 5 inhibits the serine phosphorylation and the kinase activity of Akt/PKB. As a consequence of this inhibition, Ins(1,3,4,5,6)P 5 induces apoptosis in ovarian, lung and breast cancer cells. Overexpression of constitutively active Akt protects SKBR-3 cells from Ins(1,3,4,5,6)P 5 -induced apoptosis. Furthermore, Ins(1,3,4,5,6)P 5 enhances the proapoptotic effect of cisplatin and etoposide in ovarian and lung cancer cells, respectively. These results support a role for Ins(1,3,4,5,6)P 5 as a specific inhibitor of the PI 3-K/Akt signalling pathway, that may sensitize cancer cells to the action of commonly used anticancer drugs.

In Drosophila melanogaster, mating radically transforms female physiology and behaviour. Post‐mating responses include an increase in the oviposition rate, a reduction in female receptivity and an activation of the immune system. The fitness consequences of mating are similarly dramatic – females must mate once in order to produce fertile eggs, but additional matings have a clear negative effect. Previously, microarrays have been used to examine gene expression of females differing in their reproductive status with the aim of identifying genes influenced by mating. However, as only virgin and single mated females were compared, transcriptional changes associated with reproduction (under natural selection) and male‐induced effects (possibly under sexually antagonistic selection) cannot be disentangled. We partitioned these fundamentally different effects by instead examining the expression profiles of virgin, single mated and double mated females. We found substantial effects relating to reproduction and further effects that are only attributable to mating itself. Immune response genes dominate this male‐induced effect indicating that the cost of mating may be due partly to this system’s activation. We propose that both sexually antagonistic and natural selection have been important in the evolution of the innate immunity genes, thereby contributing to the sexual dimorphism and rapid evolution at these loci.