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1.
Leukemia ; 30(7): 1502-9, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26984787

RESUMO

Chronic myeloid leukemia (CML) is characterized by expression of Bcr-abl, a tyrosine kinase oncogene. Clinical outcomes in CML were revolutionized by development of Bcr-abl-targeted tyrosine kinase inhibitors (TKIs), but CML is not cured by these agents. CML leukemia stem cells (LSCs) are relatively TKI insensitive and persist even in remission. LSC persistence results in relapse upon TKI discontinuation, or drug resistance or blast crisis (BC) during prolonged treatment. We hypothesize that increased expression of Fas-associated phosphatase 1 (Fap1) in CML contributes to LSC persistence and BC. As Fap1 substrates include Fas and glycogen synthase kinase-3ß (Gsk3ß), increased Fap1 activity in CML is anticipated to induce Fas resistance and stabilization of ß-catenin protein. Resistance to Fas-induced apoptosis may contribute to CML LSC persistence, and ß-catenin activity increases during BC. In the current study, we directly tested the role of Fap1 in CML LSC persistence using in an in vivo murine model. In TKI-treated mice, we found that inhibiting Fap1, using a tripeptide or small molecule, prevented TKI resistance, BC and relapse after TKI discontinuation; all events observed with TKI alone. In addition, Fap1 inhibition increased Fas sensitivity and decreased ß-catenin activity in CD34(+) bone marrow cells from human subjects with CML. Therapeutic Fap1 inhibition may permit TKI discontinuation and delay in progression in CML.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proteína Tirosina Fosfatase não Receptora Tipo 13/fisiologia , Animais , Apoptose/efeitos dos fármacos , Crise Blástica/etiologia , Crise Blástica/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Camundongos , Células-Tronco Neoplásicas/patologia , Domínios PDZ , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteína Tirosina Fosfatase não Receptora Tipo 13/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 13/metabolismo , Recidiva , Receptor fas/metabolismo
2.
Biophys Chem ; 32(2-3): 199-209, 1988 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-2472178

RESUMO

The complex permittivities of L-alpha-lysolecithin in the absence and presence of the gramicidin A ion channel were measured over the temperature range 0-60 degrees C and over the frequency range 1-1000 MHz. One dielectric relaxation/loss has been observed. It is located at 103.3 MHz (1.54 ns) for a micellar 0.4 M L-alpha-lysolecithin solution at 20 degrees C, whereas it is shifted to 71.7 MHz (2.22 ns) for a lamellar L-alpha-lysolecithin-gramicidin A aqueous solution (0.4 M L-alpha-lysolecithin, 0.0308 M gramicidin A) at 20 degrees C. The dielectric relaxation decreases and the relaxation time increases when gramicidin A is incorporated into L-alpha-lysolecithin. These dielectric changes are related, in part, to the micellar-to-lamellar lipid phase transition induced by the incorporation of gramicidin A into lysolecithin. We suggest that the diffuse rotational motion of the polar head group of L-alpha-lysolecithin contributes to the dielectric relaxation/loss at around 100 MHz.


Assuntos
Gramicidina , Canais Iônicos/fisiologia , Lisofosfatidilcolinas , Eletroquímica/métodos , Micelas , Modelos Teóricos , Termodinâmica
4.
Ciba Found Symp ; 192: 4-22; discussion 22-30, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-8575267

RESUMO

Owing to the presence of the recurring sequence XPGX' (where X and X' are hydrophobic residues), the molecular structure of the sequences between cross-links in elastin is viewed primarily as a series of beta-turns which become helically ordered by hydrophobic folding into beta-spirals, which in turn assemble hydrophobically into twisted filaments. Both hydrophobic folding and assembly occur when the temperature is raised above Tt, the onset of an inverse temperature transition. Using poly[fv(VPGVG),fx(VPGXG)] (where fv and fx are mole fractions with fv + fx = 1 and X is now any of the naturally occurring amino acid residues), plots of fx versus Tt result in a new hydrophobicity scale based directly on the hydrophobic folding and assembly processes of interest. With the reference values chosen at fx = 1, the most hydrophobic residues of elastin, Tyr (Y) and Phe (F), have low values of Tt, -55 and -30 degrees C, respectively, and the most hydrophilic residues, Glu (E-), Asp (D-) and Lys (K+), have high values of 250, 170 and 120 degrees C, respectively. Raising the average value of Tt for a chain or chain segment from below to above physiological temperature drives hydrophobic unfolding and disassembly; lowering Tt does the reverse. This delta Tt mechanism has been used reversibly to interconvert many energy forms and is used here to explain initiating events of elastogenesis, pulmonary emphysema, solar elastosis and the paucity of elastic fibres in scar tissue. In general, oxidation and/or photolysis convert(s) hydrophobic residues into polar residues with the consequences of irreversibly raising Tt to above 37 degrees C, hydrophobic unfolding and disassembly (fibre swelling), and greater susceptibility to proteolysis.


Assuntos
Elastina/fisiologia , Sequência de Aminoácidos , Animais , Elasticidade , Elastina/química , Humanos , Dados de Sequência Molecular , Conformação Proteica , Dobramento de Proteína
5.
Biopolymers ; 32(9): 1251-61, 1992 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-1420992

RESUMO

Relative hydrophobicities of aromatic amino acid residues are investigated by using differential scanning calorimetry (DSC) on 10 synthetic copolypentapeptides of poly(VPGVG) of elastin. Utilizing the hydrophobic-driven process of the inverse temperature transition exhibited by these polypentapeptides in aqueous solution, the relative hydrophobicities of Phe, Trp, and Tyr residues are determined by the critical temperature and heat of the transition. The DSC data for the aromatic residue containing copolypentapeptide aqueous solution indicate that tryptophan is the most hydrophobic amino acid residue, phenylalanine the third most hydrophobic on basis of transition temperature and the second on basis of transition heat. For tyrosine, significant differences are observed between the phenolic and the phenoxide anionic states. At pH 7, where tyrosine is protonated, it is found to be the second most hydrophobic amino acid residue on the basis of the transition temperature, whereas on the basis of the heat of transition, it is less hydrophobic than both tryptophan and phenylalanine. Changing the pH from pH 7 to pH 12, for example, for poly[0.8(VPGVG), 0.2(VPGYG)] in aqueous solution shifts the transition temperature from 7 to 49 degrees C with a dramatically reduced heat. On the basis of both the transition temperature scale and the heat of transition, the hydroxylated tyrosine appears less hydrophobic than glycine.


Assuntos
Aminoácidos/química , Elastina/química , Peptídeos/química , Água/química , Sequência de Aminoácidos , Varredura Diferencial de Calorimetria , Modelos Moleculares , Dados de Sequência Molecular
6.
Biopolymers ; 31(5): 465-75, 1991 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-1868163

RESUMO

Differential scanning calorimetry studies of the effect of NaCl on protein-based polymer self-assembly has been carried out on six elastin-based synthetic sequential polypeptides--i.e., the polypentapeptide (L-Val1-L-Pro2-Gly3-L-Val4-Gly5)n and its more hydrophobic analogues (L-Leu1-L-Pro2-Gly3-L-Val4-Gly5)n and (L-Val1-L-Pro2-L-Ala3-L-Val4-Gly5)n; the polytetrapeptide (L-Val1-L-Pro2-Gly3-Gly4)n and its more hydrophobic analogue (L-Ile1-L-Pro2-Gly3-Gly4)n; and the polynonapeptide (a pentatetra hybrid), (L-Val1-L-Pro2-Gly3-L-Val4-Gly5-L-Val6-L-Pro7-Gly8-Gly9++ +)n. Previous physical characterizations of the polypentapeptides have demonstrated the occurrence of an inverse temperature transition since increase in order of the polypentapeptide, as the temperature is raised from below to above that of the transition, has been repeatedly observed using different physical characterizations. In the present experiments, it is observed that the transition temperatures of the polypeptides studied are linearly dependent on NaCl concentration. The molar effectiveness of NaCl in shifting the transition temperature delta Tm/[N], is about 14 degrees C/[N], with the dependence on peptide hydrophobicity being fairly small. Interestingly, however, the delta delta Q/[N] does depend on the hydrophobicity of a polypeptide.


Assuntos
Elastina/química , Peptídeos/química , Cloreto de Sódio/química , Sequência de Aminoácidos , Varredura Diferencial de Calorimetria , Dados de Sequência Molecular , Peptídeos/síntese química , Temperatura
7.
Biopolymers ; 29(14): 1699-706, 1990 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-2207282

RESUMO

Differential scanning calorimetry studies have been carried out on the sequential polypeptide of elastin, (L-Val1-L-Pro2-Gly3-L-Val4-Gly5)n, abbreviated as PPP, and its more hydrophobic analogues (L-Leu1-L-Pro2-Gly3-L-Val4-Gly5)n, referred to as Leu1-PPP, and (L-Ile1-L-Pro2-Gly3-L-Val4-Gly5)n, referred to as Ile1-PPP Consistent with inverse temperature transitions, the temperatures of the transitions for which maximum heat absorption occurs are inversely proportional to the hydrophobicities of the polypentapeptides (31 degrees C for PPP, 16 degrees C for Leu1-PPP, and 12 degrees C for Ile1-PPP), and the endothermic heats of the transitions are small and increase with increasing hydrophobicity, i.e., 1.2, 2.9, and 3.0 kcal/mol pentamer for PPP, Leu1-PPP, and Ile1-PPP, respectively. Previous physical characterizations of the polypentapeptides have demonstrated the occurrence of an inverse temperature transition since increase in order, as the temperature is raised above that of the transition, has been repeatedly observed using different physical characterizations. Furthermore, the studies demonstrated identical conformations for PPP and Il21-PPP above and below the transition. Both heats and temperatures of the transitions vary with hydrophobicity, but not in simple proportionality.


Assuntos
Elastina , Peptídeos , Sequência de Aminoácidos , Varredura Diferencial de Calorimetria , Dados de Sequência Molecular , Temperatura , Termodinâmica
8.
Acta Crystallogr D Biol Crystallogr ; 60(Pt 9): 1606-10, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15333932

RESUMO

Binding of the BAG domain to the eukaryotic chaperone heat-shock protein (Hsp70) promotes ATP-dependent release of the protein substrate from Hsp70. Although the murine and human BAG domains have been shown to form an antiparallel three-helix bundle, the Caenorhabditis elegans BAG domain is formed by two antiparallel helices, while the third helix is extended away and stabilized by crystal-packing interactions. A small beta-sheet between helices 2 and 3 interferes with formation of the intramolecular three-helix bundle. However, intermolecular three-helix bundles are observed throughout the crystal packing and suggest that stable functional dimers and tetramers can be formed in solution. The structure may represent a new folding type of the BAG domain.


Assuntos
Proteínas de Caenorhabditis elegans/química , Caenorhabditis elegans/química , Genes bcl-2/genética , Proteínas de Choque Térmico HSP70/química , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Cristalização , Genômica , Proteínas de Choque Térmico HSP70/genética , Modelos Moleculares , Dados de Sequência Molecular , Conformação Proteica , Robótica , Difração de Raios X
9.
Biopolymers ; 32(9): 1243-50, 1992 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-1420991

RESUMO

In general, proteins fold with hydrophobic residues buried, away from water. Reversible protein folding due to hydrophobic interactions results from inverse temperature transitions where folding occurs on raising the temperature. Because homoiothermic animals constitute an infinite heat reservoir, it is the transition temperature, Tt, not the endothermic heat of the transition, that determines the hydrophobically folded state of polypeptides at body temperature. Reported here is a new hydrophobicity scale based on the values of Tt for each amino acid residue as a guest in a natural repeating peptide sequence, the high polymers of which exhibit reversible inverse temperature transitions. Significantly, a number of ways have been demonstrated for changing Tt such that reversibly lowering Tt from above to below physiological temperature becomes a means of isothermally and reversibly driving hydrophobic folding. Accordingly, controlling Tt becomes a mechanism whereby proteins can be induced to carry out isothermal free energy transduction.


Assuntos
Proteínas/química , Água/química , Sequência de Aminoácidos , Dados de Sequência Molecular , Conformação Proteica , Temperatura
10.
Int J Pept Protein Res ; 46(6): 453-63, 1995 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8748705

RESUMO

Following the nomenclature of Sandberg, the W4 sequence of human elastin, [sequence: see text], has been synthesized by solid-phase methods and characterized by carbon-13 nuclear magnetic resonance, amino-acid analysis, mass spectra and elemental analysis. This sequence was then polymerized to greater than 50 kDa as determined by retention in 50 kDa molecular weight cut-off dialysis tubing. It has been successfully cross-linked by gamma-irradiation (20 Mrad) to form an elastomeric matrix, designated as X20-poly(W4). Physical characterizations such as stress/strain, thermolelasticity, acid-base titration and inverse temperature transition studies have been carried out on this elastomer, which is homologous to the striking, poly(VPGVG), W4 sequence of bovine and porcine elastins. These results are compared with previous results on the polypentapeptide of elastin, (VPGVG)n, and it has been demonstrated that X20-poly(W4) also is a dominantly entropic elastomer. Finally, the working model for the structure of this human elastin sequence was derived computationally using molecular mechanics and dynamics calculations. Thus the human W4 sequence appears to be structurally and functionally equivalent to the bovine and porcine W4 sequences in spite of the less regular repeating pentamer sequence.


Assuntos
Elastina/síntese química , Sequência de Aminoácidos , Varredura Diferencial de Calorimetria , Elasticidade , Elastina/química , Humanos , Modelos Moleculares , Dados de Sequência Molecular
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