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Tf the primary phosphorylation of the retinoblastoma protein before the G1/S boundary is caused by the cyclin-dependent kinase (Cdks) controlled by G1 cyclins D and E. A 10 to 15-fold higher constitutive quantities of cyclin E and cyclin D1 in quiescent early-passage cells, relative to senescent cells, are found. The incapacity of senescent cells to phosphorylate the retinoblastoma protein in late G phase, may be due to the failure to activate cyclin E-Cdk2 kinase activity in these cells.

Abstract Background The β-amyloid peptide (Aβ) contains a Gly-XXX-Gly-XXX-Gly motif in its C-terminal region that has been proposed to form a "glycine zipper" that drives the formation of toxic Aβ oligomers. We have tested this hypothesis by examining the toxicity of Aβ variants containing substitutions in this motif using a neuronal cell line, primary neurons, and a transgenic C. elegans model. Results We found that a Gly37Leu substitution dramatically reduced Aβ toxicity in all models tested, as measured by cell dysfunction, cell death, synaptic alteration, or tau phosphorylation. We also demonstrated in multiple models that Aβ Gly37Leu is actually anti-toxic, thereby supporting the hypothesis that interference with glycine zipper formation blocks assembly of toxic Aβ oligomers. To test this model rigorously, we engineered second site substitutions in Aβ predicted by the glycine zipper model to compensate for the Gly37Leu substitution and expressed these in C. elegans. We show that these second site substitutions restore in vivo Aβtoxicity, further supporting the glycine zipper model. Conclusions Our structure/function studies support the view that the glycine zipper motif present in the C-terminal portion of Aβ plays an important role in the formation of toxic Aβ oligomers. Compounds designed to interfere specifically with formation of the glycine zipper could have therapeutic potential.

Senescent human diploid fibroblasts (HDF) have elevated levels of ceramide and diacylglycerol (DAG) compared with young HDF. DNA fragmentation analysis demonstrated the increased ceramide in senescent HDF was not associated with apoptosis, whereas in young HDF, exogenous ceramide induced apoptosis. In young HDF treated with both exogenous ceramide and DAG, less DNA fragmentation was observed. Thus, elevated DAG levels in senescent HDF might protect against ceramide-induced apoptosis. To determine which characteristics of senescent HDF (aging per se, cell cycle arrest, elevated [p21.sup.Sdi1,Waf1,Cip1], and senescent-like differentiation) might influence ceramide and DAG, we examined transformed or mitomycin C-treated HDF that shared some of these properties with senescent HDF. The elevation of ceramide and DAG did not depend on aging per se, cell cycle arrest, or elevation of p21. Rather, ceramide and DAG may be elevated as part of a program of differentiation that is induced by either aging or DNA damage.

NeuroD (otherwise known as BETA2) is a basic helixloop- helix (bHLH) transcription factor that is capable of converting embryonic epidermal cells into fully differentiated neurons in Xenopus embryos. In insulinoma cells, NeuroD can bind and activate the insulin promoter. When NeuroD is deleted in mice, the early differentiating pancreatic endocrine cells and a subset of the neurons in the central and peripheral nervous systems die, resulting in cellular deficits in the pancreatic islets, cerebellum, hippocampus and inner ear sensory ganglia. As a consequence, mice become diabetic and display neurological defects including ataxia and deafness. These gain-of-function and loss-of-function phenotypes suggest that NeuroD controls both common and distinct sets of molecules involved in cell survival and differentiation in different tissue types. In this review, we examine what is known about NeuroD and what remains to be answered. Understanding the primary function of NeuroD will be extremely valuable in the diagnosis and cure of the diseases that involve this transcription factor, which plays essential roles in the development and function of the pancreas and the nervous system. [ABSTRACT FROM AUTHOR]

Although there is compelling evidence that the beta amyloid peptide (Abeta) can be centrally involved in Alzheimer's disease, the natural role (if any) of this peptide remains unclear. Here we use green fluorescent protein (GFP) fusions to demonstrate that the Abeta sequence, like prion domains, can act as a modular aggregation domain when terminally appended to a normally soluble protein. We find that a single amino acid substitution (Leu(17) to Pro) in the beta peptide sequence can abolish this cis capacity to induce aggregation. Introduction of this substitution into full-length APP (i.e., a Leu(613)Pro substitution in APP695) alters the processing of APP leading to the accumulation of the C99 C-terminal fragment (CTF). We suggest that in at least some aggregation disease-related proteins the presence of an aggregation domain is not "accidental", but reflects a selected role of these domains in modulating the trafficking or metabolism of the parental protein.

NeuroD (otherwise known as BETA2) is a basic helix-loop-helix (bHLH) transcription factor that is capable of converting embryonic epidermal cells into fully differentiated neurons in Xenopus embryos. In insulinoma cells, NeuroD can bind and activate the insulin promoter. When NeuroD is deleted in mice, the early differentiating pancreatic endocrine cells and a subset of the neurons in the central and peripheral nervous systems die, resulting in cellular deficits in the pancreatic islets, cerebellum, hippocampus and inner ear sensory ganglia. As a consequence, mice become diabetic and display neurological defects including ataxia and deafness. These gain-of-function and loss-of-function phenotypes suggest that NeuroD controls both common and distinct sets of molecules involved in cell survival and differentiation in different tissue types. In this review, we examine what is known about NeuroD and what remains to be answered. Understanding the primary function of NeuroD will be extremely valuable in the diagnosis and cure of the diseases that involve this transcription factor, which plays essential roles in the development and function of the pancreas and the nervous system.