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2.  Poriferan survivin exhibits a conserved regulatory role in the interconnected pathways of cell cycle and apoptosis 
Cell Death and Differentiation  2010;18(2):201-213.
Survivin orchestrates intracellular pathways during cell division and apoptosis. Its central function as mitotic regulator and inhibitor of cell death has major implications for tumor cell proliferation. Analyses in early-branching Metazoa so far propose an exclusive role of survivin as a chromosomal passenger protein, whereas only later during evolution a complementary antiapoptotic function might have arisen, concurrent with increased organismal complexity. To lift the veil on the ancestral function(s) of this key regulator, a survivin-like protein (SURVL) of one of the earliest-branching metazoan taxa was identified and functionally characterized. SURVL of the sponge Suberites domuncula shares considerable similarities with its metazoan homologs, ranging from conserved exon/intron structure to presence of protein-interaction domains. Whereas sponge tissue shows a low steady-state level, SURVL expression was significantly upregulated in rapidly proliferating primmorph cells. In addition, challenge of tissue and primmorphs with heavy metal or lipopeptide stimulated SURVL expression, concurrent with the expression of a newly discovered caspase. Complementary functional analyses in transfected HEK-293 cells revealed that heterologous expression of a SURVL–EFGP fusion not only promotes proliferation but also enhances resistance to cadmium-induced cell death. Taken together, these results suggest both a deep evolutionary conserved dual role of survivin and an equally conserved central position in the interconnected pathways of cell cycle and apoptosis.
PMCID: PMC3131884  PMID: 20651742
survivin; IAP; caspase; sponges; Suberites domuncula; cadmium
3.  An otoprotective role for the apoptosis inhibitor protein survivin 
Cell Death & Disease  2010;1(7):e51-.
Hearing impairment caused by ototoxic insults, such as noise or gentamicin is a worldwide health problem. As the molecular circuitries involved are not yet resolved, current otoprotective therapies are rather empirical than rational. Here, immunohistochemistry and western blotting showed that the cytoprotective protein survivin is expressed in the human and guinea pig cochlea. In the guinea pig model, moderate noise exposure causing only a temporary hearing impairment transiently evoked survivin expression in the spiral ligament, nerve fibers and the organ of Corti. Mechanistically, survivin upregulation may involve nitric oxide (NO)-induced Akt signaling, as enhanced expression of the endothelial NO synthase and phosphorylated Akt were detectable in some surviving-positive cell types. In contrast, intratympanic gentamicin injection inducing cell damage and permanent hearing loss correlated with attenuated survivin levels in the cochlea. Subsequently, the protective activity of the human and the guinea pig survivin orthologs against the ototoxin gentamicin was demonstrated by ectopic overexpression and RNAi-mediated depletion studies in auditory cells in vitro. These data suggest that survivin represents an innate cytoprotective resistor against stress conditions in the auditory system. The pharmacogenetic modulation of survivin may thus provide the conceptual basis for the rational design of novel therapeutic otoprotective strategies.
PMCID: PMC3032560  PMID: 21364656
Auditory system; aminoglycoside antibiotics; chromosomal passenger complex; cochlea; nitric oxide; ototoxicity
4.  Physiological and pathological changes in the redox state of human serum albumin critically influence its binding properties 
British Journal of Pharmacology  2007;151(5):580-590.
Binding and transport of a number of endogenous and exogenous compounds is an important function of the main plasma protein, albumin. In vivo and in vitro, albumin may be oxidatively modified in different ways with different agents at different sites. These modifications have various consequences on the physiological functions of albumin. Diabetes mellitus, liver diseases and nephropathy are just a few examples of disorders in which oxidative stress is involved and altered albumin functions have been described. This review is focussed on the consequences of oxidative modification on the binding properties of albumin. These range from no effect to decreased or increased binding affinities depending on the ligand under investigation and the type of modification. Indicators for modification include glycosylation, disulphide formation or the content of carbonyl groups. The redox state of albumin can affect the binding properties in several ways, including altered conformation and consequently altered affinities at binding sites and altered binding when the binding reaction itself is redox sensitive. The physiological or pathophysiological concentrations of different oxidatively modified albumin molecules vary over a wide range and are crucial in assessing the clinical relevance of altered ligand binding properties of a particularly modified albumin species in various disease conditions.
PMCID: PMC2013999  PMID: 17471184
albumin; mercaptalbumin; ligand binding; oxidative stress; glycosylation
5.  Recurrent Salmonella enteritidis sepsis and hepatic tuberculosis. 
Gut  1995;37(1):136-139.
A 33 year old woman with recurrent Salmonella enteritidis sepsis is described. Penicillins, ceftriaxone, ciprofloxacin, and chloramphenicol could not eradicate the salmonellas but a combination of high dose ciprofloxacin and ceftriaxone for the eighth episode successfully cured the infection. The combination of ciprofloxacin and ceftriaxone may be a valuable therapeutic regimen in patients with recurrent salmonella sepsis. Prolonged intrahepatic cholestasis resulting from granulomatous hepatitis in this patient improved considerably with empiric ursodeoxycholic acid treatment. A liver biopsy specimen showing non-caseating epitheloid granulomas was positive for mycobacterial DNA by polymerase chain reaction. Repeated bronchoscopy with multiple biopsies eventually revealed caseating granulomas with acid fast bacilli in the lung biopsy specimens. Therefore, tuberculosis was diagnosed as the underlying disease and the cause of granulomatous hepatitis in this patient and tuberculostatic treatment was started. Polymerase chain reaction for mycobacterial DNA may be helpful in the differential diagnosis of hepatic granulomas when routine histological examination and culture of biopsy specimens are not diagnostic. Tuberculosis should be considered as one of the diseases predisposing to recurrent salmonella sepsis.
PMCID: PMC1382785  PMID: 7672664
6.  Analysis of murine coronavirus surface glycoprotein functions by using monoclonal antibodies. 
Journal of Virology  1991;65(1):254-262.
The murine coronavirus surface glycoprotein gene was expressed as a fusion protein in bacteria, and the expressed protein was used to generate S protein-specific monoclonal antibodies (MAbs). Three of the MAbs, 11F, 30B, and 10G, were able to neutralize virus infectivity, and two of them, 11F and 10G, were able to block virus-induced, cell-to-cell fusion. The binding sites of the 11F, 30B, and 10G MAbs were determined by Western immunoblotting and epitope mapping. The 11F and 30B MAbs bound to sites located, respectively, between amino acids 33 to 40 and 395 to 406 in the amino-terminal (S1) subunit of the S protein, and the 10G MAb bound to a site located between amino acids 1123 and 1137 in the carboxy-terminal (S2) subunit. These data define more precisely the interactions between the S1 and S2 subunits of the murine coronavirus S protein and provide further insights into its structure and function.
PMCID: PMC240512  PMID: 1985201

Results 1-6 (6)