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1.
Expert Rev Anticancer Ther ; 14(3): 251-4, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24397833

RESUMO

Multiple myeloma (MM) remains incurable, and ultimately, patients exhibit disease progression under current treatment regimens. Proteasome inhibitors have emerged as frontline treatment of relapsed and refractory MM however, resistance to these drugs occur through poorly defined mechanisms. Numerous studies have identified different acquired resistance models such as ß5 proteasome subunit mutations and stabilization of tumor suppressors and apoptotic proteins. In addition, recent findings have identified a progenitor organization in MM whereby early progenitor tumor cells show resistance to proteasome inhibitor therapy and cause progressive disease with maturation arrest. This editorial highlights the potential causes of MM relapse in the context of these tumor progenitor cells and the role these cells play in treatment failure.


Assuntos
Antineoplásicos/farmacologia , Mieloma Múltiplo/patologia , Inibidores de Proteassoma/farmacologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Células-Tronco Neoplásicas/metabolismo , Recidiva
2.
J Biol Chem ; 286(50): 43081-90, 2011 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-22016389

RESUMO

Nickel delivery during maturation of Escherichia coli [NiFe] hydrogenase 3 includes the accessory proteins HypA, HypB, and SlyD. Although the isolated proteins have been characterized, little is known about how they interact with each other and the hydrogenase 3 large subunit, HycE. In this study the complexes of HypA and HycE were investigated after modification with the Strep-tag II. Multiprotein complexes containing HypA, HypB, SlyD, and HycE were observed, consistent with the assembly of a single nickel insertion cluster. An interaction between HypA and HycE did not require the other nickel insertion proteins, but HypB was not found with the large subunit in the absence of HypA. The HypA-HycE complex was not detected in the absence of the HypC or HypD proteins, involved in the preceding iron insertion step, and this interaction is enhanced by nickel brought into the cell by the NikABCDE membrane transporter. Furthermore, without the hydrogenase 1, 2, and 3 large subunits, complexes between HypA, HypB, and SlyD were observed. These results support the hypothesis that HypA acts as a scaffold for assembly of the nickel insertion proteins with the hydrogenase precursor protein after delivery of the iron center. At different stages of the hydrogenase maturation process, HypA was observed at or near the cell membrane by using fluorescence confocal microscopy, as was HycE, suggesting membrane localization of the nickel insertion event.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas de Escherichia coli/metabolismo , Hidrogenase/metabolismo , Níquel/metabolismo , Western Blotting , Proteínas de Transporte/genética , Eletroforese em Gel de Poliacrilamida , Proteínas de Escherichia coli/genética , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Hidrogenase/genética , Peptídeos e Proteínas de Sinalização Intracelular , Microscopia de Fluorescência , Peptidilprolil Isomerase/genética , Peptidilprolil Isomerase/metabolismo , Ligação Proteica , Espectrometria de Massas em Tandem
3.
Nat Prod Rep ; 27(5): 681-94, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20442959

RESUMO

Microorganisms have evolved to utilize nickel ions in several different enzyme systems that enable these organisms to survive and proliferate in various environments. Typically the biosynthesis of these nickel containing enzymes are multi-step processes involving a number of accessory proteins, with one or more proteins dedicated to the delivery of the cognate nickel ion to the active site of the enzyme. This review highlights the nickel proteins dedicated to the biogenesis of [NiFe]-hydrogenase, urease, and carbon monoxide dehydrogenase, and aims to summarize our current knowledge of these unique proteins. Putative proteins that function in excess nickel storage and/or detoxification, through sequestration of considerable amount of nickel, are also discussed.


Assuntos
Bactérias , Proteínas de Bactérias/metabolismo , Níquel/metabolismo , Bactérias/enzimologia , Bactérias/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos
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