Homeostasis under hypoxic conditions is maintained through a coordinated transcriptional response mediated by the hypoxia-inducible factor (HIF) pathway and requires coactivation by the CBP and p300 transcriptional coactivators. Through a target-based high-throughput screen, we identified chetomin as a disrupter of HIF binding to p300. At a molecular level, chetomin disrupts the structure of the CH1 domain of p300 and precludes its interaction with HIF, thereby attenuating hypoxia-inducible transcription. Systemic administration of chetomin inhibited hypoxia-inducible transcription within tumors and inhibited tumor growth. These results demonstrate a therapeutic window for pharmacological attenuation of HIF activity and further establish the feasibility of disrupting a signal transduction pathway by targeting the function of a transcriptional coactivator with a small molecule.

Hematopoietic stem cells (HSC) are tightly regulated through, as yet, undefined mechanisms that balance self-renewal and differentiation. We have identified a role for the transcriptional coactivators CREB-binding protein (CBP) and p300 in such HSC fate decisions. A full dose of CBP, but not p300, is crucial for HSC self-renewal. Conversely, p300, but not CBP, is essential for proper hematopoietic differentiation. Furthermore, in chimeric mice, hematologic malignancies emerged from both CBP ؊/؊ and p300 ؊/؊ cell populations. Thus, CBP and p300 play essential but distinct roles in maintaining normal hematopoiesis, and, in mice, both are required for preventing hematologic tumorigenesis.

The Drosophila melanogaster ovary is a powerful yet simple system with only a few cell types. Cell death in the ovary can be induced in response to multiple developmental and environmental signals. These cell deaths occur at distinct stages of oogenesis and involve unique mechanisms utilizing apoptotic, autophagic and perhaps necrotic processes. In this review, we summarize recent progress characterizing cell death mechanisms in the fly ovary.

DNA fragmentation is a critical component of apoptosis but it has not been characterized in non-apoptotic forms of cell death, such as necrosis and autophagic cell death. In mammalian apoptosis, caspase activated DNase (CAD) cleaves DNA into nucleosomal fragments in dying cells, and subsequently DNaseII, an acid nuclease, completes the DNA degradation but acts non-cell-autonomously within lysosomes of engulfing cells. Here we examine the requirement for DNases during two examples of programmed cell death (PCD) that occur in the Drosophila melanogaster ovary, starvation-induced death of mid-stage egg chambers and developmental nurse cell death in late oogenesis. Surprisingly, we found that DNaseII was required cell-autonomously in nurse cells during developmental PCD, indicating that it acts within dying cells. Dying nurse cells contain autophagosomes, indicating that autophagy may contribute to these forms of PCD. Furthermore, we provide evidence that developmental nurse cell PCD in late oogenesis shows hallmarks of necrosis. These findings indicate that DNaseII can act cell-autonomously to degrade DNA during non-apoptotic cell death.

SUMMARYThe Bcl-2 family has been shown to regulate mitochondrial dynamics during cell death in mammals and C. elegans, but evidence for this in Drosophila has been elusive. Here, we investigate the regulation of mitochondrial dynamics during germline cell death in the Drosophila melanogaster ovary. We find that mitochondria undergo a series of events during the progression of cell death, with remodeling, cluster formation and uptake of clusters by somatic follicle cells. These mitochondrial dynamics are dependent on caspases, the Bcl-2 family, the mitochondrial fission and fusion machinery, and the autophagy machinery. Furthermore, Bcl-2 family mutants show a striking defect in cell death in the ovary. These data indicate that a mitochondrial pathway is a major mechanism for activation of cell death in Drosophila oogenesis.

Recent studies have indicated that polarized light may be useful in the discrimination between benign and malignant moles. In fact, imaging polarimetry could provide nonmvasive diagnosis ofa range ofdermatological disease states. However, in order to design an efficacious sensor for clinical use, the complete polarization-altering properties ofa particular disease must be well understood. We present Mueller matrix imaging polarimetryas atechnique for characterizing various dermatological diseases. PreliminaryMueller matrix imagery at 633 nm suggests that both malignant moles and lupus lesions maybe identified through polarimetric measurements. Malignant moles are found to be less depolarizing than the surrounding tissues, and lupus lesions are found to have rapidly varying retardance orientation.

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