Alzheimer's disease is characterized by neurodegeneration and deposition of A4, a peptide that is proteolytically released from the amyloid precursor protein (APP). Missense mutations in the genes coding for APP and for the polytopic membrane proteins presenilin (PS) 1 and PS2 have been linked to familial forms of early-onset Alzheimer's disease. Overexpression of presenilins, especially that of PS2, induces increased susceptibility for apoptosis that is even more pronounced in cells expressing presenilin mutants. Additionally, presenilins themselves are targets for activated caspases in apoptotic cells. When we analyzed APP in COS-7 cells overexpressing PS2, we observed proteolytic processing close to the APP carboxyl terminus. Proteolytic conversion was increased in the presence of PS2-I, which encodes one of the known PS2 pathogenic muta- Neurodegeneration in selected brain regions is one of the pathological features of Alzheimer's disease, together with amyloid deposition in extracellular plaques, congophilic angiopathy, and intracellular tangles. Amyloid deposited in senile plaques is mainly composed of A4, a peptide consisting of 40 -42 residues, which derives by proteolytic processing from its cognate precursor protein termed APP 1 (1). Mutations in the APP gene cause a rare form of early-onset familial Alzheimer's disease (FAD) by raising the levels of total A4 or by increasing the ratio of the longer form of A4 that ends at residue 42 to the form ending at residue 40 (2-5). Additionally, the expression of APP carrying those mutations has been reported to induce apoptosis in cells, suggesting a probable link between apoptotic pathways and neurodegeneration in Alzheimer's disease (6 -8).Mutations causative for the majority of FAD cases have been identified recently in genes encoding presenilin (PS) 1 and PS2 (9 -11). Missense mutations in these genes were also found to alter APP processing in a pathological manner by increasing the relative concentration of A4 ending at residue 42 (12-16). Both proteins are endoproteolytically converted by two alternative pathways: (i) in the first pathway, cleavage occurs within a highly hydrophobic region of the presenilins (16 -18), and (ii) in the second pathway, presenilins become converted by caspase-3 family proteases at about 30 residues distal to the normal cleavage site (19 -20). The corresponding caspase-derived fragments have been detected in all tissues and stages of animal development, suggesting a role of PS processing in the cellular response to apoptotic signals (19,21). Furthermore, overexpression of PS2 in transfected cells has been shown to increase susceptibility to apoptotic cell death. The latter is even more pronounced in cells expressing mutant PS2-I that encodes one of the known PS2 missense mutations changing Asn 141 into Ile (22, 23).When we analyzed carboxyl-terminal fragments of APP in cells coexpressing PS2 or PS2-I, we observed proteolytic processing of APP within the cytoplasmic domain that was augmented for mutated PS2-I (see below)....
Hydra provides an interesting developmental model system where pattern formation processes are easily accessible to experimentation during regeneration. Previous studies have shown that the neuropeptide head activator affects cellular growth and head-specific cellular differentiation during head regeneration and budding. In order to investigate the signal transduction pathway and the regulatory genes involved in these processes, we measured cAMP levels after head activator treatment and found that head activator leads to an increase in cAMP levels at concentrations where effects on nerve cell determination and differentiation are observed (10(−11) to 10(−9) M). Moreover, exposure of intact hydra to a permeable form of cAMP stimulates nerve-cell differentiation and thus mimicks the effect of endogenous head activator. Band-shift assays were performed to detect changes in hydra nuclear protein binding activity during regeneration or after head activator treatment. We found that the cAMP response element (CRE) promotes a specific and strong DNA-binding activity which is dramatically enhanced and modified during early regeneration or after HA treatment. We also identified a surprisingly highly conserved hydra gene encoding the cAMP Response Element Binding protein, which is involved in this CRE-binding activity. Initiation of regeneration upon wounding provokes an endogenous release of HA which leads to the final differentiation of determined nerve cells. We propose that the nerve-cell differentiation observed within the first 4–8 hours of regeneration relies on the agonist effect of head activator on the cAMP pathway, which would in turn modulate the CRE-binding activity of the hydra CREB protein and thus regulate the transcriptional activity of genes involved in regeneration processes.
A Synthetic Approach to Study the Structural Biology of Tat Proteins from HIV-1 and EIAV -(6 refs.). -(KRAFT, M.; SCHUCKERT, O.; WALLACH, J.; WESTENDROP, M. O.; BAYER, P.; ROESCH, P.; FRANK, R. W.; Pept.: Chem., Struct. Biol., Proc. Am. Pept. Symp., 14th (1995) 21-23; Edited by Kaumaya, P. T. P.; Hodges, R. S.; Mayflower Sci., Kingswinford, UK; EN)
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