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Tumor suppressor proteins are the main cellular barrier opposing neoplastic transformation. Among these host molecules, retinoblastoma protein (RB) plays a central role. A novel insight is now advanced to suggest that various inhibitors of insulin and insulin-like growth factor (IGF) signalling such as the putative tumor suppressor insulin-degrading enzyme (IDE) as well as the anti-oncogenic proteins PTEN and insulin-like growth factor-binding protein 7 (IGFBP-7) serve the common goal of ensuring that RB remains active. Since, moreover, IDE and IGFBP-7 each potentially achieves RB protection through preventing both binding and inactivation of RB by insulin, IGF-1 or IGF-2, the present perception also vindicates the importance of previous findings on the physical interaction of any of these growth factors with RB for cell fate. Notably, the therapeutic counterpart of this natural principle for maintaining or restoring RB function through insulin/IGF neutralization is the innovative class of anti-cancer agents termed MCR peptides and developed over the past decade.

Prion diseases are transmissible, neurodegenerative disorders associated with as yet incompletely defined isoforms of a cellular protein termed prion protein (PrP). We have now identified in PrP structural information compatible with nucleotide- and nucleic acid-binding. As such, PrP contains a putative nicotinamide adenine dinucleotide (NADH)-binding site. Moreover, the PrP octarepeats reveal homology to the nucleic acid-binding and strand-annealing octarepeats of mammalian heterogeneous ribonucleoprotein (RNP) A1. Therefore, PrP may have NADH-dependent oxidoreductase activity as well as A1-like functions such as nucleic acid annealing and splicing. Moreover, we propose that infectious prions are propagated through a dynamic molecular symbiosis between a ribozyme-like nucleic acid and a conformational isomer of the RNP-like prion protein. Thus, our model has important implications for the understanding and treatment of prion diseases.

Previous studies have demonstrated the presence of the insulin receptor in the cell nucleus. Recently, it was shown that the insulin receptor also exhibits nuclear tyrosine kinase activity. In the present investigation, I have searched for structural correlates to a nuclear localization of the insulin receptor as well as to other potential nuclear actions of this molecule. Interestingly, this analysis yielded that the insulin receptor (alpha-subunit) contains a bipartite nuclear localization signal (consistent with the preceding experimental data), several zinc finger-like motifs and an RGG box. These findings have intriguing implications with regard to a presumable role of the insulin receptor (alpha-subunit) as a gene regulatory molecule.

Environmental challenges appear to elicit similar patterns of cellular responses such as positive autoregulation and autoamplification whether one considers the generation of antibodies with identical antigen specificity or the accumulation of host-protective transcription factors. Therefore, I analyzed the structure of immunoglobulins (Ig) for motifs commonly found in transcription factors. Specifically, the well-known abundance and periodic location of cysteine residues in immunoglobulin chains prompted me to check antibody constant regions for the presence of putative metal-binding domains and zinc finger-like sequences. The constant regions of Ig light and heavy chains were found to harbor one or several copies, respectively, of a short cysteine- and histidine-containing sequence. Moreover, all four IgG subclasses were detected to comprise zinc finger-like motifs in their heavy chain constant and hinge domains. Yet another finding is the occurrence of several sequences of the form serine-proline-X-X and/or threonine-proline-X-X in the hinge sections of IgA and IgG3. These results suggest that antibody constant regions, as a fragment and/or embedded in a full-length immunoglobulin chain, may complex metal, thus acquiring conformations conducive to dimerization and nucleic acid binding. As such, my study provides a putative structural basis for the known requirement of divalent metal cations, particularly of zinc ions, for a normal immune response, and warrants further investigations, both theoretical and experimental, into the potential of antibody constant regions for metal binding and gene regulation. Moreover, future testing of the proposed zinc finger peptides from Ig constant domains should yield information relevant to zinc finger design with potentially wide applications in research and clinical medicine.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study reports structural similarities between viral oncoproteins, growth factors belonging to the insulin family, members of the steroid/thyroid receptor superfamily, a D-type cyclin, the Elf-1 transcription factor and Bcl oncoproteins in regions that have been shown or proposed to mediate complex formation of these proteins with the tumor suppressor retinoblastoma protein (RB). This relationship predicts a common intracellular pathway for mitogenic signals and molecules promoting cell survival. Conversely, the structural evidence described here suggests that RB may play a central role both at the boundary between negative and positive cell growth regulation as well as in developmental decisions between cell death and cell survival.

The present study proposes a novel type of synthetic chimaeric polypeptides potentially useful in the therapy of various diseases. The prototype peptide termed 'synthetic inducible biological response amplifier' (SIBRA) would comprise a ligand-binding site, a DNA-binding region, a trans-activating domain as well as strings of residues ensuring bioavailability and targeting to specific compartments such as the cell nucleus. These domains would be selected from cellular proteins, artificially tailored to a SIBRA and further modified towards a molecule with both in vivo and intracellular activity. Since proposed to resemble a host molecule with autoregulatory properties, a SIBRA would be activated upon exposure to a defined environmental stimulus and amplify host responses appropriate for this stimulus. Proteins would accumulate that share functional domains with the administered SIBRA and have a positive autoregulatory capacity. The latter may involve the interaction of the induced protein with the promoter of its gene resulting in a direct positive autoregulatory loop or require the induction of intermediary proteins that eventually upregulate the production of SIBRA-like host proteins. Since the ligand-binding site of a SIBRA is rationally designed to target a pathogenic protein, SIBRAs could be regarded as the product of an artificial acceleration and refinement of strategies intrinsic to the immune system.