Molecular basis of inherited predispositions for tumors

On the basis of literature data and own experience the authors review the current knowledge about the molecular basis of inherited predispositions for tumors. They hypothesize that in the near perspective 5-10 years studies using existing registry data/material and the latest novel technology will allow the identification of the molecular background for the majority of hereditary cancers which will have enormous practical consequences especially for the prevention of malignancies.     

The presence of the WGD motif in CC8 heterodimeric disintegrin increases its inhibitory effect on alphaII(b)beta3, alpha(v)beta3, and alpha5beta1 integrins

Two highly homologous dimeric disintegrins, CC5 and CC8, have been isolated from the venom of the North African sand viper Cerastes cerastes. CC5 is a homodimer containing an RGD motif in its subunits. CC8 is a heterodimer. The CC8A and CC8B subunits contain RGD and WGD tripeptide sequence in their respective integrin-binding loops. Both CC5 and CC8 inhibited platelet aggregation and the adhesion of cells expressing integrins alphaII(b)beta3, alpha(v)beta3, and alpha5beta1 to appropriate ligands. However, the inhibitory activity of CC8 was at least 1 order of magnitude higher than that of CC5. Enhanced activity of CC8 over CC5 was also observed in the induction of LIBS epitopes on beta1 and beta3 integrins. Synthetic peptides in which the arginyl residue of the RGD motif had been replaced with tryptophans exhibited increased inhibitory activity toward integrins alpha5beta1, alphaII(b)beta3, and alpha(v)beta3. Moreover, alanine substitution of the aspartic acid of the WGD motif of these peptides decreased their inhibitory ability, whereas the same substitution in the RGD sequence almost completely abolished the activity of the peptides. We conclude that the WGD motif enhances the inhibitory activity of disintegrins toward alphaII(b)beta3, alpha(v)beta3, and alpha5beta1 integrins.     

Regulation of apoptosis by the ubiquitin and proteasome pathway

Regulated proteolysis plays important roles in cell physiology as well as in pathological conditions. In most of the cases, regulated proteolysis is carried out by the ubiquitin- and proteasome-dependent proteolytic system, which is also in charge of the bulk of cytoplasmic proteolysis. However, apoptosis or the process of programmed cell death is regulated by a different proteolytic system, i.e . by caspases, a family of specialized cysteine proteases. Nevertheless, there is plenty of evidence of a crosstalk between the apoptotic pathways and the ubiquitin and proteasome system, whose function in apoptosis appears to be very complex. Proteasome inhibitors induce apoptosis in multiple cell types, while in other they are relatively harmless or even prevent apoptosis induced by other stimuli. Proteasomes degrade specific proteins during apoptosis, but on the other hand some components of the proteasome system are degraded by caspases. The knowledge about the involvement of the ubiquitin- and proteasome-dependent system in apoptosis is already clinically exploited, since proteasome inhibitors are being tested as experimental drugs in the treatment of cancer and other pathological conditions, where manipulation of apoptosis is desirable.     

Molecular simulation study of cooperativity in hydrophobic association: clusters of four hydrophobic particles

The multibody contribution to the potential of mean force (PMF) of hydrophobic association of four methane molecules in water was investigated by means of umbrella-sampling molecular dynamics. Two systems were considered: (i). a trigonal pyramid with three methane molecules at contact distance forming a fixed base, the fourth molecule being placed on the top with variable distance from the base; and (ii). a regular uniformly expanding tetrahedron. Methane-methane distances as far as 12.5 A, i.e. beyond the second solvent-separated minimum of the PMF, were considered to address the baseline problem. In contrast to the small effect in the three-body case studied previously (Protein Sci 9 (2000) 1235), the multibody contribution was found to amount to approximately 0.2 kcal/mol per methane-methane pair, or approximately 25% of the depth of the contact minimum in the PMF. The main effect of the multibody contribution to the PMF is a reduction of the height of the barrier between the contact and solvent separated minima and a narrowing of the region of its maximum, while the region of the contact minimum is affected only weakly. The reduction of the barrier is due to four-body contributions. The cooperative contributions to the PMF agree very well with those computed from the molecular surface of the systems under consideration, which further supports earlier observations that the molecular surface can be used with good accuracy to describe the energetics of hydrophobic association.     

Computer Modeling of the Solution Conformation of Cyclic Enkephalins

The probable conformations of two cyclic enkephalin analogs, DNS-cyclo[D-Dab-Gly-Trp-Leu] (I) and DNS-cyclo[D-Dab-Gly-Trp-D-Leu] (II) (DNS = dansyl), were determined by combining the results of NOE, vicinal coupling constant and fluorescence energy transfer measurements with theoretical calculations. The common feature of the conformations for both peptides is the presence of a -turn at residues 2 and 3.     

Vasopressin V2 Receptor/Bioligand Interactions

We predict some essential interactions between the V2 vasopressin renal receptor (V2R) and its agonists [Arg⁸]vasopressin (AVP) and [D-Arg⁸]vasopressin (DAVP), and the non-peptide antagonist OPC-31260. V2R controls antidiuresis and belongs to the superfamily of heptahelical transmembrane (7TM) G-protein-coupled receptors (GPCRs). The receptor was built, the ligands were docked and the structures relaxed using advanced molecular modeling techniques. Docked agonists and antagonists appear to prefer similar V2R compartments. A number of receptor amino acid residues are indicated, mainly in the TM3–TM7 helices, as potentially important in ligand binding. Many of these residues are invariant for either the GPCR superfamily or the subfamily of related (vasopressin V2R, V1aR and V1bR and oxytocin OR) receptors. Moreover, some of the equivalent residues in V1aR have already been found critical for ligand affinity [Mouillac et al., J. Biol. Chem., 270 (1995) 25771].     

Computer Modeling of the Solution Conformation of Cyclic Enkephalins

Summary The probable conformations of two cyclic enkephalin analogs, DNS-cyclo[d-Dab-Gly-Trp-Leu] (I) and DNS-cyclo[d-Dab-Gly-Trp-d-Leu] (II) (DNS=dansyl), were determined by combining the results of NOE, vicinal coupling constant and fluorescence energy transfer measurements with theoretical calculations. The common feature of the conformations for both peptides is the presence of a β-turn at residues 2 and 3.     

The role of erythropoietin and its receptor in growth,survival and therapeutic response of human tumor cells: From clinic to bench — a critical review

Recombinant human erythropoietin (rhEPO) has been used clinically to alleviate cancer- and chemotherapy-related anemia. However, recent clinical trials have reported that rhEPO also may adversely impact disease progression and survival. The expression of functional EPO receptors (EPOR) has been demonstrated in many human cancer cells where, at least in vitro, rhEPO can stimulate cell growth and survival and may induce resistance to selected therapies.     

Lipase-catalyzed regioselective synthesis of steryl (6′-<Emphasis Type="Italic">O</Emphasis>-acyl)glucosides

The regioselective acylation of cholesteryl β-d-glucoside, at the C-6 of the glucose moiety, was achieved using microbial lipases in organic solvents. With palmitic acid as an acyl donor 81 or 63% conversions of cholesteryl glucoside to its 6′-O-palmitoyl derivative were obtained using Candida antarctica or Rhizomucor miehei enzymes, respectively. High yields (64–92%) were also obtained with fatty acids 6:0–22:0 and 16:1 (n-7). The synthesis of cholesteryl (6′-O-palmitoyl)glucoside was also achieved via transesterification, using mono-, di- and tri-palmitoylglycerols or methyl and ethyl palmitate as acyl sources. With R. miehei lipase transesterification between methyl palmitate (80 mM) and cholesteryl glucoside (1 mM) proceeded after 24 h with a nearly quantitative yield (97%).