Cellular and Molecular Life Sciences

Balashov, S.; Lanyi, J.

doi: 10.1007/s00018-007-7167-ypmid: 17571211

Retinal proteins function as photoreceptors and ion pumps. Xanthorhodopsin of Salinibacter ruber is a recent addition to this diverse family. Its novel and distinctive feature is a second chromophore, a carotenoid, which serves as light-harvesting antenna. Here we discuss the properties of this carotenoid/retinal complex most relevant to its function (such as the specific binding site controlled by the retinal) and its relationship to other retinal proteins (bacteriorhodopsin, archaerhodopsin, proteorhodopsin and retinal photoreceptors of archaea and eukaryotes). Antenna addition to a retinal protein has not been observed among the archaea and emerged in bacteria apparently in response to environmental conditions where light-harvesting becomes a limiting factor in retinal protein functioning.

Milleron, R.; Bratton, S.

doi: 10.1007/s00018-007-7135-6pmid: 17572850

Hippocrates’ assertion that ‘what the lance does not heal, fire will’ underscores the fact that for thousands of years heat has been used to treat a variety of diseases, including cancer. Indeed, spontaneous tumor remission has been observed in patients following feverish infection [1], and expression of activated oncogenes, such as Ras, can render tumor cells sensitive to heat compared with normal cells [2, 3]. In the past, a primary drawback to the use of heat as a clinical therapy was the inability to selectively focus heat to tumors in situ. Of late, however, several approaches have been devised to deliver heat more precisely, including the use of heated nanoparticles, making hyperthermia a more clinically tractable treatment option [4, 5]. Despite these practical advances, the mechanisms responsible for heat shock-induced cell death remain controversial and ill-defined. In this Visions and Reflections we discuss recent findings surrounding the initiation of heat shock-induced apoptosis, and propose future areas of research.

Baud’huin, M.; Lamoureux, F.; Duplomb, L.; Rédini, F.; Heymann, D.

doi: 10.1007/s00018-007-7104-0pmid: 17530461

1997 saw the identification of a novel set of proteins within the tumor necrosis factor (TNF)/TNF receptor families that are required for the control of bone remodeling. Therefore, these receptors, receptor activator of nuclear factor kappa B (RANK), osteoprotegerin (OPG) and their ligand RANK ligand (RANKL) became the critical molecular triad controlling osteoclastogenesis and pathophysiologic bone remodeling. However, the establishment of the corresponding knock-out and transgenic mice revealed unexpected results, most particularly, the involvement of these factors in the vascular system and immunity. Thus, the OPG/RANK/RANKL molecular triad appears to be associated with vascular calcifications and plays a pivotal function in the development of the immune system through dendritic cells. OPG/RANK/RANKL thus constitute a molecular bridge spanning bone metabolism, vascular biology and immunity. This review summarizes recent knowledge of OPG/RANK/RANKL interactions and activities as well as the current evidence for their participation in osteoimmunology and vascular diseases. In fine, the targeting of the OPG/RANK/RANKL axis as novel therapeutic approaches will be discussed.

Sokolowska, M.; Kaus-Drobek, M.; Czapinska, H.; Tamulaitis, G.; Siksnys, V.; Bochtler, M.

doi: 10.1007/s00018-007-7124-9pmid: 17568994

It has long been known that most Type II restriction endonucleases share a conserved core fold and similar active-sites. The same core folding motif is also present in the MutH protein, a component of the bacterial DNA mismatch repair machinery. In contrast to most Type II restriction endonucleases, which assemble into functional dimers and catalyze double-strand breaks, MutH is a monomer and nicks hemimethylated DNA. Recent biochemical and crystallographic studies demonstrate that the restriction enzymes BcnI and MvaI share many additional features with MutH-like proteins, but not with most other restriction endonucleases. The structurally similar monomers all recognize approximately symmetric target sequences asymmetrically. Differential sensitivities to slight substrate asymmetries, which could be altered by protein engineering, determine whether the enzymes catalyze only single-strand nicks or double-strand breaks.

Breuleux, M.

doi: 10.1007/s00018-007-7120-0pmid: 17530167

Heregulin (HRG) is a soluble secreted growth factor, which, upon binding and activation of ErbB3 and ErbB4 transmembrane receptor tyrosine kinases, is involved in cell proliferation, invasion, survival and differentiation of normal and malignant tissues. The HRG gene family consists of four members: HRG-1, HRG-2, HRG-3 and HRG-4, of which a multitude of different isoforms are synthesized by alternative exon splicing, showing various tissue distribution and biological activities. Disruption of the physiological balance between HRG ligands and their ErbB receptors is implicated in the formation of a variety of human cancers. The general mechanisms involved in HRG-induced tumorigenesis is discussed.

Spagnoli, F.

doi: 10.1007/s00018-007-7184-xpmid: 17565443

The formation of the vertebrate pancreas is a complex process that typifies the basic steps of embryonic development. It involves the establishment of competence, specification, signaling from neighboring tissues, morphogenesis, and the elaboration of tissue-specific genetic networks. A full analysis of this multistep process will help us to understand classic principles of embryonic development. Furthermore, this will provide the blueprint for experimental programming of pancreas formation from embryonic stem cells in the context of diabetes cell-therapy. Although in the past decade many studies have contributed to a solid foundation for understanding pancreatogenesis, important gaps persist in our knowledge of early pancreas formation. This review will summarize the current understanding of the early mechanisms coming into play to pattern the “pre-pancreatic” region within the endoderm and, gradually, specify the pancreatic tissue.

Lowe, D. B.; Shearer, M. H.; Jumper, C. A.; Kennedy, R. C.

doi: 10.1007/s00018-007-7165-0pmid: 17565444

.Cancer immunotherapy faces many obstacles that include eliciting immune reactions to self antigens as well as overcoming tumor-derived immunosuppressive networks and evasion tactics. Within the vaccine arsenal for inhibiting cancer proliferation, plasmid DNA represents a novel immunization strategy that is capable of eliciting both humoral and cellular arms of the immune response in addition to being safely administered and easily engineered and manufactured. Unfortunately, while DNA vaccines have performed well in preventing and treating malignancies in animal models, their overall application in human clinical trials has not impacted cancer regression to date. Since the establishment of these early trials, progress has been made in terms of increasing DNA vaccine immunogenicity and subverting the suppressive properties of tumor cells. Therefore, the success of future plasmid DNA use in cancer patients will depend on combinatorial strategies that enhance and direct the DNA vaccine immune response while also targeting tumor evasion mechanisms.

Späth, B.; Canino, G.; Marchfelder, A.

doi: 10.1007/s00018-007-7160-5pmid: 17599240

Although the enzyme tRNase Z has only recently been isolated, a plethora of data has already been acquired concerning the enzyme. tRNase Z is the endonuclease that catalyzes the removal of the tRNA 3′ trailer, yielding the mature tRNA 3′ end ready for CCA addition and aminoacylation. Another substrate cleaved by tRNase Z is the small chromogenic phosphodiester bis(p-nitrophenyl)phosphate (bpNPP), which is the smallest tRNase Z substrate known so far. Hitherto the biological function as tRNA 3′-end processing enzyme has been shown only in one prokaryotic and one eukaryotic organism, respectively. This review summarizes the present information concerning the two tRNase Z substrates pre-tRNA and bpNPP, as well as the metal requirements of tRNase Z enzymes.

Wu, B.; Beitz, E.

doi: 10.1007/s00018-007-7163-2pmid: 17571212

The aquaporin protein family generally seems to be designed for the selective passage of water or glycerol. Charged molecules, metal ions and even protons are strictly excluded. Recently, particular aquaporin isoforms were reported to conduct unconventional permeants, i.e., the unpolar gases carbon dioxide and nitric oxide, the polar gas ammonia, the oxidative oxygen species hydrogen peroxide, and the metalloids antimonite, arsenite and silicic acid. Here, we summarize the available data on permeability properties and physiological settings of these aquaporins and we analyze which structural features might be connected to permeability for non-water, non-glycerol solutes.

Hemberger, M.

doi: 10.1007/s00018-007-7113-zpmid: 17585370

Formation of extraembryonic tissues, and in particular the placenta, is an absolute necessity to ensure growth and survival of the embryo during intrauterine development in mammals. To date, an intriguing number of genes have been identified that are essential for development of extraembryonic structures. However, the underlying genetic information must be interpreted by a set of epigenetic instructions to both establish and maintain lineage- and cell type-specific expression profiles. Based on accumulating data in particular from studies in the mouse, this article is aimed at highlighting the epigenetic machinery required for differentiation of extraembryonic cell types and formation of the placenta. An overview of knockout models reveals key stages in extraembryonic development that are particularly sensitive to alterations in the chromatin environment. The article also summarizes the importance of complex epigenetically controlled mechanisms for placental development, such as imprinted gene expression and imprinted X chromosome inactivation. These investigations of the epigenetic regulation of transcriptional states will provide valuable insights into the dynamic chromatin environment that is specific to extraembryonic tissues and determines gene expression patterns required for normal trophoblast differentiation.