The corepressor complex that includes Ebi and SMRTER is a target of epidermal growth factor (EGF) and Notch signaling pathways and regulates Delta (Dl)‐mediated induction of support cells adjacent to photoreceptor neurons of the Drosophila eye. We describe a mechanism by which the Ebi/SMRTER corepressor complex maintains Dl expression. We identified a gene, charlatan (chn), which encodes a C2H2‐type zinc‐finger protein resembling human neuronal restricted silencing factor/repressor element RE‐1 silencing transcription factor (NRSF/REST). The Ebi/SMRTER corepressor complex represses chn transcription by competing with the activation complex that includes the Notch intracellular domain (NICD). Chn represses Dl expression and is critical for the initiation of eye development. Thus, under EGF signaling, double negative regulation mediated by the Ebi/SMRTER corepressor complex and an NRSF/REST‐like factor, Chn, maintains inductive activity in developing photoreceptor cells by promoting Dl expression.

No abstract

Allelic mutants exhibiting growth defects in Drosophila were isolated. Molecular cloning identified the responsible gene as a budding yeast Tim50 ortholog, and thus it was named tiny tim 50 (ttm50). The weak allele (ttm50 Gp99) produced small flies due to reduced cell size and number, and growth terminated at the larval stage in the strong alleles (ttm50 IE1 and ttm50 IE2). Twin-spot analysis showed fewer cells in ttm50 Gp99clones, whereas ttm50 IE1 clones did not proliferate, suggesting that the gene has an essential cellular function. Tim50 is known to maintain mitochondrial membrane potential (MMP) while facilitating innermembrane protein transport. We found that tagged Ttm50 also localized to mitochondria and that mitochondrial morphology and MMP were affected in mutants, indicating that mitochondrial dysfunction causes the developmental phenotype. Conversely, ttm50 overexpression increased MMP and apoptosis. Co-expression of p35 suppressed this apoptosis, resulting in cell overproliferation. Interestingly, ttm50 transcription was tissue specific, corresponding to elevated MMP in the larval midgut, which was decreased in the mutant. The correlation of ttm50 expression levels with differences in MMP match its proposed role in mitochondrial permeability barrier maintenance. Thus a mitochondrial protein translocase component can play active roles in regulating metabolic levels, possibly for modulation of physiological function or growth in development.

The O-type forkhead domain transcription factor (FOXO) is involved in many biological processes such as aging, the oxidative stress response, and growth regulation. FOXO activity is tightly controlled within cells. In particular, growth factor signaling pathways and the oxidative stress response can both stimulate nuclear translocation of this transcription factor. Here, we show that tetrahydrocurcumin (THC), a curcumin metabolite, regulates the oxidative stress response and aging via FOXO. In NIH3T3 cells, THC induced nuclear accumulation of FOXO4, a member of the FOXO family of transcription factors, by inhibiting phosphorylation of protein kinase B (PKB)/Akt. In Drosophila melanogaster, THC attenuated the oxidative stress response, an effect that was blocked in a foxo mutant background. THC also extended the life span of Drosophila under normal conditions, and loss of either foxo or Sir2 activity eliminated this effect. Based on these results, THC may regulate the aging process via an evolutionarily conserved signaling pathway that includes both foxo and Sir2.

A lterations in the ABL tyrosine kinase are characteristic genetic events in multiple forms of leukemia. In humans, leukemogenic forms of ABL arise from chromosomal translocations. In the resulting fusion proteins, residues encoded by the first exon of ABL are replaced by sequence from the BCR protein, resulting in 185-kDa and 210-kDa isoforms or, less frequently, from the TEL protein (1). In chronic myelogenous leukemia, p210 BCR͞ABL is found in 95% of all cases (2). These same hybrid proteins can transform cultured cells and induce leukemia in mice. ABL sequences encoding tyrosine kinase activity are essential for transformation (3)(4)(5). Also present are ABL regulatory sequences, including Src homology (SH)3, SH2, and actin-binding domains. The fusion of ABL with BCR leads to increased kinase activity and an apparent shift in subcellular localization (6), changes that alter the magnitude and characteristics of downstream signals.BCR͞ABL-induced transformation depends on its continued expression (7-9). Dominant negative-acting proteins that block BCR͞ABL-mediated transformation of cultured cells have been described (10)(11)(12)(13)(14). These proteins typically rely on disruption of broadly used signaling components required indirectly for BCR͞ ABL function. Ideally, an effective BCR͞ABL inhibitor should directly suppress the activity that most closely correlates with transformation. The ABL kinase-specific inhibitor STI-571, for instance, has shown promise as an effective BCR͞ABL-suppressing drug (15).We propose an alternate approach to inhibition of BCR͞ABL and downstream pathways, using modular peptides to combine tyrosine phosphatase and ABL-binding functions resulting in efficient ABL-targeted tyrosine phosphatases.Protein tyrosine phosphatases (PTPs) (16, 17) might act as BCR͞ABL inhibitors through the dephosphorylation of ABL and͞or its substrates. Overexpression of PTP1B inhibit fibroblast transformation by p210 BCR͞ABL (18), and this effect may be caused, in part, by direct dephosphorylation of BCR͞ABL (19). SHP1 (SHPTP1) also can interact with and partially inhibit the function of c-ABL (20) and BCR͞ABL (21). These phosphatases may be endogenous down-regulators of ABL that can inhibit BCR͞ABL. Their effectiveness as BCR͞ABL suppressers is moderate, however, and may be tempered by deleterious effects from overexpression. The inhibition potency of these phosphatases might be improved markedly if they could be liberated from normal regulation and targeted to BCR͞ABL.RIN1 is both a substrate and binding partner of ABL (22). RIN1 also interacts with BCR͞ABL, and this association is detected in leukemia-derived cell (23). The ABL binding domain (ABD) of RIN1 interacts with both the SH3 and SH2 domains of ABL (ref.23; this work). We have used the RIN1-ABD as an ''escort'' peptide to deliver the SHP1 tyrosine phosphatase catalytic domain to BCR͞ABL. The resulting escort͞inhibitor (ABD͞SHP1c) showed potent suppressive activity against BCR͞ABL in a variety of assays including leukemogenesis. These results sug...

Sensory organs are constantly exposed to physical and chemical stresses that collectively threaten the survival of sensory neurons. Failure to protect stressed neurons leads to age-related loss of neurons and sensory dysfunction in organs in which the supply of new sensory neurons is limited, such as the human auditory system. Transducin β-like protein 1 (TBL1) is a candidate gene for ocular albinism with late-onset sensorineural deafness, a form of X-linked age-related hearing loss. TBL1 encodes an evolutionarily conserved F-box–like and WD40 repeats–containing subunit of the nuclear receptor co-repressor/silencing mediator for retinoid and thyroid hormone receptor and other transcriptional co-repressor complexes. Here we report that a Drosophila homologue of TBL1, Ebi, is required for maintenance of photoreceptor neurons. Loss of ebi function caused late-onset neuronal apoptosis in the retina and increased sensitivity to oxidative stress. Ebi formed a complex with activator protein 1 (AP-1) and was required for repression of Drosophila pro-apoptotic and anti-apoptotic genes expression. These results suggest that Ebi/AP-1 suppresses basal transcription levels of apoptotic genes and thereby protects sensory neurons from degeneration.

Alzheimer's disease (AD) is the most epidemic neuronal dysfunctions among elderly people. It is accompanied by neuronal disorders along with learning and memory defects, as well as massive neurodegeneration phenotype. The presence of intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques, called senile plaques (SPs), and brain atrophy are typically observed in the brains of AD patients. It has been over 20 years since the discovery that small peptide, called beta-amyloid (Aβ), has pivotal role for the disease formation. Since then, a variety of drugs have been developed to cure AD; however, there is currently no effective drug for the disorder. This therapeutic void reflects lacks of ideal model system, which can evaluate the progression of AD in a short period. Recently, large numbers of AD model system have been established using Drosophila melanogaster by overproducing Aβ molecules in the brain. These systems successfully reflect some of the symptoms along with AD. In this review, we would like to point out "pros and cons" of Drosophila AD models.

Increasing evidence indicates that defects in the sensory system are highly correlated with age-related neurodegenerative diseases, including Alzheimer's disease (AD). This raises the possibility that sensory cells possess some commonalities with neurons and may provide a tool for studying AD. The sensory system, especially the auditory system, has the advantage that depression in function over time can easily be measured with electrophysiological methods. To establish a new mouse AD model that takes advantage of this benefit, we produced transgenic mice expressing amyloid-β (Aβ), a causative element for AD, in their auditory hair cells. Electrophysiological assessment indicated that these mice had hearing impairment, specifically in high-frequency sound perception (>32 kHz), at 4 months after birth. Furthermore, loss of hair cells in the basal region of the cochlea, which is known to be associated with age-related hearing loss, appeared to be involved in this hearing defect. Interestingly, overexpression of human microtubule-associated protein tau, another factor in AD development, synergistically enhanced the Aβ-induced hearing defects. These results suggest that our new system reflects some, if not all, aspects of AD progression and, therefore, could complement the traditional AD mouse model to monitor Aβ-induced neuronal dysfunction quantitatively over time.