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1.
Genes Dev ; 30(8): 960-72, 2016 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-27056667

RESUMEN

In complex with the cosubstrate UDP-N-acetylglucosamine (UDP-GlcNAc),O-linked-GlcNAc transferase (OGT) catalyzes Ser/ThrO-GlcNAcylation of many cellular proteins and proteolysis of the transcriptional coregulator HCF-1. Such a dual glycosyltransferase-protease activity, which occurs in the same active site, is unprecedented and integrates both reversible and irreversible forms of protein post-translational modification within one enzyme. Although occurring within the same active site, we show here that glycosylation and proteolysis occur through separable mechanisms. OGT consists of tetratricopeptide repeat (TPR) and catalytic domains, which, together with UDP-GlcNAc, are required for both glycosylation and proteolysis. Nevertheless, a specific TPR domain contact with the HCF-1 substrate is critical for proteolysis but not Ser/Thr glycosylation. In contrast, key catalytic domain residues and even a UDP-GlcNAc oxygen important for Ser/Thr glycosylation are irrelevant for proteolysis. Thus, from a dual glycosyltransferase-protease, essentially single-activity enzymes can be engineered both in vitro and in vivo. Curiously, whereas OGT-mediated HCF-1 proteolysis is limited to vertebrate species, invertebrate OGTs can cleave human HCF-1. We present a model for the evolution of HCF-1 proteolysis by OGT.


Asunto(s)
Factor C1 de la Célula Huésped/metabolismo , N-Acetilglucosaminiltransferasas/metabolismo , Proteolisis , Secuencias de Aminoácidos , Animales , Dominio Catalítico , Simulación por Computador , Evolución Molecular , Humanos , Invertebrados/enzimología , Modelos Moleculares , Mutación , Procesamiento Proteico-Postraduccional , Estructura Terciaria de Proteína
2.
J Biol Chem ; 293(46): 17754-17768, 2018 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-30224358

RESUMEN

O-Linked GlcNAc transferase (OGT) possesses dual glycosyltransferase-protease activities. OGT thereby stably glycosylates serines and threonines of numerous proteins and, via a transient glutamate glycosylation, cleaves a single known substrate-the so-called HCF-1PRO repeat of the transcriptional co-regulator host-cell factor 1 (HCF-1). Here, we probed the relationship between these distinct glycosylation and proteolytic activities. For proteolysis, the HCF-1PRO repeat possesses an important extended threonine-rich region that is tightly bound by the OGT tetratricopeptide-repeat (TPR) region. We report that linkage of this HCF-1PRO-repeat, threonine-rich region to heterologous substrate sequences also potentiates robust serine glycosylation with the otherwise poor Rp-αS-UDP-GlcNAc diastereomer phosphorothioate and UDP-5S-GlcNAc OGT co-substrates. Furthermore, it potentiated proteolysis of a non-HCF-1PRO-repeat cleavage sequence, provided it contained an appropriately positioned glutamate residue. Using serine- or glutamate-containing HCF-1PRO-repeat sequences, we show that proposed OGT-based or UDP-GlcNAc-based serine-acceptor residue activation mechanisms can be circumvented independently, but not when disrupted together. In contrast, disruption of both proposed activation mechanisms even in combination did not inhibit OGT-mediated proteolysis. These results reveal a multiplicity of OGT glycosylation strategies, some leading to proteolysis, which could be targets of alternative molecular regulatory strategies.


Asunto(s)
Endopeptidasas/metabolismo , Factor C1 de la Célula Huésped/metabolismo , N-Acetilglucosaminiltransferasas/metabolismo , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Endopeptidasas/genética , Glicosilación , Factor C1 de la Célula Huésped/genética , Humanos , Simulación de Dinámica Molecular , Enzimas Multifuncionales/genética , Enzimas Multifuncionales/metabolismo , Mutación , N-Acetilglucosaminiltransferasas/genética , Proteolisis , Estereoisomerismo , Especificidad por Sustrato , Uridina Difosfato N-Acetilglucosamina/análogos & derivados , Uridina Difosfato N-Acetilglucosamina/metabolismo
3.
Bioorg Med Chem ; 22(4): 1450-8, 2014 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-24457091

RESUMEN

A series of degrasyn-like symmetrical compounds have been designed, synthesized, and screened against B cell malignancy (multiple myeloma, mantle cell lymphoma) cell lines. The lead compounds T5165804 and CP2005 showed higher nanomolar potency against these tumor cells in comparison to degrasyn and inhibited Usp9x activity in vitro and in intact cells. These observations suggest that this new class of compounds holds promise as cancer therapeutic agents.


Asunto(s)
Antineoplásicos/química , Nitrilos/química , Piridinas/química , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cianoacrilatos , Dimerización , Humanos , Modelos Moleculares , Mieloma Múltiple/tratamiento farmacológico , Nitrilos/farmacología , Nitrilos/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Ubiquitina Tiolesterasa/metabolismo
4.
Blood ; 117(11): 3151-62, 2011 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-21248063

RESUMEN

Although chronic myelogenous leukemia (CML) is effectively controlled by Bcr-Abl kinase inhibitors, resistance to inhibitors, progressive disease, and incomplete eradication of Bcr-Abl-expressing cells are concerns for the long-term control and suppression of this disease. We describe a novel approach to targeting key proteins in CML cells with a ubiquitin-cycle inhibitor, WP1130. Bcr-Abl is rapidly modified with K63-linked ubiquitin polymers in WP1130-treated CML cells, resulting in its accumulation in aggresomes, where is it unable to conduct signal transduction. Induction of apoptosis because of aggresomal compartmentalization of Bcr-Abl was observed in both imatinib-sensitive and -resistant cells. WP1130, but not Bcr-Abl kinase inhibitors, directly inhibits Usp9x deubiquitinase activity, resulting in the down-regulation of the prosurvival protein Mcl-1 and facilitating apoptosis. These results demonstrate that ubiquitin-cycle inhibition represents a novel and effective approach to blocking Bcr-Abl kinase signaling and reducing Mcl-1 levels to engage CML cell apoptosis. This approach may be a therapeutic option for kinase inhibitor-resistant CML patients.


Asunto(s)
Apoptosis , Proteínas de Fusión bcr-abl/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Transducción de Señal , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Ubiquitinación , Apoptosis/efectos de los fármacos , Benzamidas , Línea Celular Tumoral , Cianoacrilatos , Resistencia a Antineoplásicos/efectos de los fármacos , Endopeptidasas/metabolismo , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Humanos , Mesilato de Imatinib , Modelos Biológicos , Nitrilos/farmacología , Fosforilación/efectos de los fármacos , Piperazinas/farmacología , Transporte de Proteínas/efectos de los fármacos , Piridinas/farmacología , Pirimidinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Especificidad por Sustrato/efectos de los fármacos , Ubiquitina Tiolesterasa/metabolismo , Ubiquitinación/efectos de los fármacos
5.
Infect Immun ; 79(12): 4850-7, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21911458

RESUMEN

Macrophages are key mediators of antimicrobial defense and innate immunity. Innate intracellular defense mechanisms can be rapidly regulated at the posttranslational level by the coordinated addition and removal of ubiquitin by ubiquitin ligases and deubiquitinases (DUBs). While ubiquitin ligases have been extensively studied, the contribution of DUBs to macrophage innate immune function is incompletely defined. We therefore employed a small molecule DUB inhibitor, WP1130, to probe the role of DUBs in the macrophage response to bacterial infection. Treatment of activated bone marrow-derived macrophages (BMM) with WP1130 significantly augmented killing of the intracellular bacterial pathogen Listeria monocytogenes. WP1130 also induced killing of phagosome-restricted bacteria, implicating a bactericidal mechanism associated with the phagosome, such as the inducible nitric oxide synthase (iNOS). WP1130 had a minimal antimicrobial effect in macrophages lacking iNOS, indicating that iNOS is an effector mechanism for WP1130-mediated bacterial killing. Although overall iNOS levels were not notably different, we found that WP1130 significantly increased colocalization of iNOS with the Listeria-containing phagosome during infection. Taken together, our data indicate that the deubiquitinase inhibitor WP1130 increases bacterial killing in macrophages by enhancing iNOS localization to the phagosome and suggest a potential role for ubiquitin regulation in iNOS trafficking.


Asunto(s)
Macrófagos/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Nitrilos/farmacología , Fagosomas/enzimología , Inhibidores de Proteasas/farmacología , Piridinas/farmacología , Animales , Línea Celular , Cianoacrilatos , Endopeptidasas/metabolismo , Escherichia coli/fisiología , Listeria monocytogenes/fisiología , Macrófagos/enzimología , Ratones , Óxido Nítrico Sintasa de Tipo II/genética , Transporte de Proteínas/efectos de los fármacos , Ubiquitina/metabolismo
6.
Immunol Invest ; 38(3-4): 240-54, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19811435

RESUMEN

Polymorphisms in the TNF-alpha and TNF receptor type 2 (TNFR2) genes in Asian Indians are not well understood. We investigated single nucleotide polymorphisms in the TNF-alpha 5'-flanking promoter/enhancer region and in exons 6, 9 and 10 of TNFR2 gene by PCR-restriction length polymorphism (PCR-RFLP) and PCR-sequence specific primer (SSP) techniques, respectively. The results showed single bi-allelic polymorphism in TNF-alpha (-308G > A) and in TNFR2 exons 6 (676 T > G) and 9 (1176 G > A). Additionally, three bi-allelic polymorphisms (1663 G > A, 1668G > T and 1690C > T) were observed in the exon 10 of TNFR2 gene. The distribution of polymorphic alleles distinctly differed in Aryan and Dravidian Indian communities. The TNF-alpha and TNFR2 genotype and allele frequencies of Asian Indians stand closer to other Asian populations but distant from Caucasians. Furthermore, TNF-alpha -308 GA genotype was associated with significantly higher production of TNF-alpha as compared to GG genotype. These polymorphisms may be related to variation in TNF-alpha and TNFR2 expression during immune response to various stimuli in Asian Indians.


Asunto(s)
Pueblo Asiatico/genética , Polimorfismo de Nucleótido Simple , Receptores Tipo II del Factor de Necrosis Tumoral/genética , Factor de Necrosis Tumoral alfa/genética , Adulto , Anciano , Ensayo de Inmunoadsorción Enzimática , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , India , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Factor de Necrosis Tumoral alfa/biosíntesis , Adulto Joven
7.
Open Biol ; 7(6)2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28659383

RESUMEN

O-linked N-acetylglucosamine (O-GlcNAc) is an essential and dynamic post-translational modification found on hundreds of nucleocytoplasmic proteins in metazoa. Although a single enzyme, O-GlcNAc transferase (OGT), generates the entire cytosolic O-GlcNAc proteome, it is not understood how it recognizes its protein substrates, targeting only a fraction of serines/threonines in the metazoan proteome for glycosylation. We describe a trapped complex of human OGT with the C-terminal domain of TAB1, a key innate immunity-signalling O-GlcNAc protein, revealing extensive interactions with the tetratricopeptide repeats of OGT. Confirmed by mutagenesis, this interaction suggests that glycosylation substrate specificity is achieved by recognition of a degenerate sequon in the active site combined with an extended conformation C-terminal of the O-GlcNAc target site.


Asunto(s)
N-Acetilglucosaminiltransferasas/metabolismo , Repeticiones de Tetratricopéptidos/fisiología , Proteínas Adaptadoras Transductoras de Señales/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales/genética , Secuencia de Aminoácidos , Glicosilación , Humanos , N-Acetilglucosaminiltransferasas/genética , Alineación de Secuencia , Especificidad por Sustrato , Repeticiones de Tetratricopéptidos/genética
8.
PLoS One ; 10(8): e0136636, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26305326

RESUMEN

Human HCF-1 (also referred to as HCFC-1) is a transcriptional co-regulator that undergoes a complex maturation process involving extensive O-GlcNAcylation and site-specific proteolysis. HCF-1 proteolysis results in two active, noncovalently associated HCF-1N and HCF-1C subunits that regulate distinct phases of the cell-division cycle. HCF-1 O-GlcNAcylation and site-specific proteolysis are both catalyzed by O-GlcNAc transferase (OGT), which thus displays an unusual dual enzymatic activity. OGT cleaves HCF-1 at six highly conserved 26 amino acid repeat sequences called HCF-1PRO repeats. Here we characterize the substrate requirements for OGT cleavage of HCF-1. We show that the HCF-1PRO-repeat cleavage signal possesses particular OGT-binding properties. The glutamate residue at the cleavage site that is intimately involved in the cleavage reaction specifically inhibits association with OGT and its bound cofactor UDP-GlcNAc. Further, we identify a novel OGT-binding sequence nearby the first HCF-1PRO-repeat cleavage signal that enhances cleavage. These results demonstrate that distinct OGT-binding sites in HCF-1 promote proteolysis, and provide novel insights into the mechanism of this unusual protease activity.


Asunto(s)
Factor C1 de la Célula Huésped/metabolismo , N-Acetilglucosaminiltransferasas/metabolismo , Subunidades de Proteína/metabolismo , Proteolisis , Transcripción Genética , Sitios de Unión , Citocinesis/genética , Ácido Glutámico/metabolismo , Células HeLa , Factor C1 de la Célula Huésped/genética , Humanos , N-Acetilglucosaminiltransferasas/genética , Subunidades de Proteína/genética , Secuencias Repetitivas de Aminoácido/genética
9.
Science ; 342(6163): 1235-9, 2013 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-24311690

RESUMEN

Host cell factor-1 (HCF-1), a transcriptional co-regulator of human cell-cycle progression, undergoes proteolytic maturation in which any of six repeated sequences is cleaved by the nutrient-responsive glycosyltransferase, O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). We report that the tetratricopeptide-repeat domain of O-GlcNAc transferase binds the carboxyl-terminal portion of an HCF-1 proteolytic repeat such that the cleavage region lies in the glycosyltransferase active site above uridine diphosphate-GlcNAc. The conformation is similar to that of a glycosylation-competent peptide substrate. Cleavage occurs between cysteine and glutamate residues and results in a pyroglutamate product. Conversion of the cleavage site glutamate into serine converts an HCF-1 proteolytic repeat into a glycosylation substrate. Thus, protein glycosylation and HCF-1 cleavage occur in the same active site.


Asunto(s)
Factor C1 de la Célula Huésped/química , Factor C1 de la Célula Huésped/metabolismo , N-Acetilglucosaminiltransferasas/química , N-Acetilglucosaminiltransferasas/metabolismo , Secuencias de Aminoácidos , Sustitución de Aminoácidos , Dominio Catalítico , Cristalografía por Rayos X , Glicosilación , Humanos , Enlace de Hidrógeno , Modelos Moleculares , Conformación Proteica , Estructura Terciaria de Proteína , Proteolisis , Ácido Pirrolidona Carboxílico/metabolismo , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Uridina Difosfato N-Acetilglucosamina/química , Uridina Difosfato N-Acetilglucosamina/metabolismo
10.
Biochem Pharmacol ; 82(4): 341-9, 2011 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-21621524

RESUMEN

Ubiquitin-activating enzyme 1 (UBE1) is a critical regulator of the ubiquitination cycle and its targeted inhibition may be an appropriate therapeutic strategy as tumor cells are reported to have increased dependence on protein ubiquitination. PYR-41 is a small molecule with previously described UBE1 inhibitory activity. PYR-41 blocks ubiquitination reactions but paradoxically leads to the accumulation of high MW ubiquitinated proteins. Detailed evaluation of PYR-41 activity demonstrated that PYR-41 inhibited UBE1 activity but also had equal or greater inhibitory activity against several deubiquitinases (DUBs) in intact cells and purified USP5 in vitro. Both UBE1 and DUB inhibition were mediated through PYR-41-induced covalent protein cross-linking which paralleled the inhibition of the target proteins enzymatic activity. PYR-41 also mediated cross-linking of specific protein kinases (Bcr-Abl, Jak2) to inhibit their signaling activity. Chemical reactivity modeling provided some insight into the cross-linking potential and partial target selectivity of PYR-41. Overall, our results suggest a broader range of targets and a novel mechanism of action for this UBE1 inhibitor. In addition, since PYR-41-related compounds have demonstrated anti-tumor activity in animal studies, partially selective protein cross-linking may represent an alternate approach to affect signal transduction modules and ubiquitin cycle-regulatory proteins for cancer therapy.


Asunto(s)
Antineoplásicos/metabolismo , Benzoatos/metabolismo , Reactivos de Enlaces Cruzados/metabolismo , Furanos/metabolismo , Pirazoles/metabolismo , Enzimas Activadoras de Ubiquitina/antagonistas & inhibidores , Enzimas Activadoras de Ubiquitina/metabolismo , Proteínas Ubiquitinadas/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , Benzoatos/química , Benzoatos/farmacología , Reactivos de Enlaces Cruzados/química , Reactivos de Enlaces Cruzados/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Furanos/química , Furanos/farmacología , Células HEK293 , Humanos , Células K562 , Pirazoles/química , Pirazoles/farmacología , Proteínas Ubiquitinadas/química
11.
Cell Signal ; 23(12): 2076-85, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21855629

RESUMEN

AG490 is a tyrosine kinase inhibitor with activity against Jak2 and apoptotic activity in specific leukemias. Due to its weak kinase inhibitory activity and poor pharmacology, we conducted a cell-based screen for derivatives with improved Jak2 inhibition and activity in animals. Two hits emerged from an initial small chemical library screen, and more detailed structure-activity relationship studies led to the development of WP1130 with 50-fold greater activity in suppressing Jak2-dependent cytokine signaling than AG490. However, WP1130 did not directly suppress Jak2 kinase activity, but mediated Jak2 ubiquitination resulting in its trafficking through HDAC6 to perinuclear aggresomes without cytokine stimulation or SOCS-1 induction. Jak2 primarily contained K63-linked ubiquitin polymers, and mutation of this lysine blocked Jak2 ubiquitination and mobilization in WP1130-treated cells. Further analysis demonstrated that WP1130, but not AG490, acts as a deubiquitinating enzyme (DUB) inhibitor, possibly through a Michael addition reaction. We conclude that chemical modification of AG490 resulted in development of a DUB inhibitor with activity against a DUB capable of modulating Jak2 ubiquitination, trafficking and signal transduction.


Asunto(s)
Endopeptidasas/metabolismo , Janus Quinasa 2/metabolismo , Inhibidores de Proteasas/farmacología , Transducción de Señal/efectos de los fármacos , Tirfostinos/farmacología , Ubiquitinación , Sustitución de Aminoácidos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cianoacrilatos , Evaluación Preclínica de Medicamentos , Endopeptidasas/química , Pruebas de Enzimas , Proteínas HSP90 de Choque Térmico/metabolismo , Histona Desacetilasa 6 , Histona Desacetilasas/metabolismo , Humanos , Concentración 50 Inhibidora , Interleucina-6/farmacología , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Nitrilos/farmacología , Fosforilación , Inhibidores de Proteasoma , Transporte de Proteínas/efectos de los fármacos , Proteolisis , Piridinas/farmacología , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT5/metabolismo , Ubiquitina/genética , Ubiquitina/metabolismo
12.
Cancer Res ; 70(22): 9265-76, 2010 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-21045142

RESUMEN

Recent evidence suggests that several deubiquitinases (DUB) are overexpressed or activated in tumor cells and many contribute to the transformed phenotype. Agents with DUB inhibitory activity may therefore have therapeutic value. In this study, we describe the mechanism of action of WP1130, a small molecule derived from a compound with Janus-activated kinase 2 (JAK2) kinase inhibitory activity. WP1130 induces rapid accumulation of polyubiquitinated (K48/K63-linked) proteins into juxtanuclear aggresomes, without affecting 20S proteasome activity. WP1130 acts as a partly selective DUB inhibitor, directly inhibiting DUB activity of USP9x, USP5, USP14, and UCH37, which are known to regulate survival protein stability and 26S proteasome function. WP1130-mediated inhibition of tumor-activated DUBs results in downregulation of antiapoptotic and upregulation of proapoptotic proteins, such as MCL-1 and p53. Our results show that chemical modification of a previously described JAK2 inhibitor results in the unexpected discovery of a novel DUB inhibitor with a unique antitumor mechanism.


Asunto(s)
Apoptosis/efectos de los fármacos , Cuerpos de Inclusión/efectos de los fármacos , Nitrilos/farmacología , Piridinas/farmacología , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Western Blotting , Carboxipeptidasas/antagonistas & inhibidores , Carboxipeptidasas/genética , Carboxipeptidasas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cianoacrilatos , Endopeptidasas/genética , Endopeptidasas/metabolismo , Células HEK293 , Humanos , Microscopía Confocal , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Interferencia de ARN , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitina/metabolismo , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo
13.
Blood ; 109(8): 3470-8, 2007 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-17202319

RESUMEN

Imatinib mesylate (Gleevec) is effective therapy against Philadelphia chromosome-positive leukemia, but resistance develops in all phases of the disease. Bcr/Abl point mutations and other alterations reduce the kinase inhibitory activity of imatinib mesylate; thus, agents that target Bcr/Abl through unique mechanisms may be needed. Here we describe the activity of WP1130, a small molecule that specifically and rapidly down-regulates both wild-type and mutant Bcr/Abl protein without affecting bcr/abl gene expression in chronic myelogenous leukemia (CML) cells. Loss of Bcr/Abl protein correlated with the onset of apoptosis and reduced phosphorylation of Bcr/Abl substrates. WP1130 did not affect Hsp90/Hsp70 ratios within the cells and did not require the participation of the proteasomal pathway for loss of Bcr/Abl protein. WP1130 was more effective in reducing leukemic versus normal hematopoietic colony formation and strongly inhibited colony formation of cells derived from patients with T315I mutant Bcr/Abl-expressing CML in blast crisis. WP1130 suppressed the growth of K562 heterotransplanted tumors as well as both wild-type Bcr/Abl and T315I mutant Bcr/Abl-expressing BaF/3 cells transplanted into nude mice. Collectively, our results demonstrate that WP1130 reduces wild-type and T315I mutant Bcr/Abl protein levels in CML cells through a unique mechanism and may be useful in treating CML.


Asunto(s)
Apoptosis/efectos de los fármacos , Crisis Blástica/tratamiento farmacológico , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Nitrilos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Animales , Apoptosis/genética , Benzamidas , Crisis Blástica/enzimología , Crisis Blástica/genética , Crisis Blástica/patología , Línea Celular Tumoral , Cianoacrilatos , Ensayos de Selección de Medicamentos Antitumorales , Proteínas de Fusión bcr-abl/biosíntesis , Proteínas de Fusión bcr-abl/genética , Regulación Enzimológica de la Expresión Génica , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Ratones , Ratones Desnudos , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/enzimología , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Piperazinas/farmacología , Mutación Puntual , Pirimidinas/farmacología , Ensayo de Tumor de Célula Madre
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