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1.
J Biol Chem ; 283(31): 21394-403, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18480060

RESUMO

Cells with functional DNA mismatch repair (MMR) stimulate G(2) cell cycle checkpoint arrest and apoptosis in response to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). MMR-deficient cells fail to detect MNNG-induced DNA damage, resulting in the survival of "mutator" cells. The retrograde (nucleus-to-cytoplasm) signaling that initiates MMR-dependent G(2) arrest and cell death remains undefined. Since MMR-dependent phosphorylation and stabilization of p53 were noted, we investigated its role(s) in G(2) arrest and apoptosis. Loss of p53 function by E6 expression, dominant-negative p53, or stable p53 knockdown failed to prevent MMR-dependent G(2) arrest, apoptosis, or lethality. MMR-dependent c-Abl-mediated p73alpha and GADD45alpha protein up-regulation after MNNG exposure prompted us to examine c-Abl/p73alpha/GADD45alpha signaling in cell death responses. STI571 (Gleevec, a c-Abl tyrosine kinase inhibitor) and stable c-Abl, p73alpha, and GADD45alpha knockdown prevented MMR-dependent apoptosis. Interestingly, stable p73alpha knockdown blocked MMR-dependent apoptosis, but not G(2) arrest, thereby uncoupling G(2) arrest from lethality. Thus, MMR-dependent intrinsic apoptosis is p53-independent, but stimulated by hMLH1/c-Abl/p73alpha/GADD45alpha retrograde signaling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose , Proteínas de Ciclo Celular/metabolismo , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-abl/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Relação Dose-Resposta a Droga , Fase G2 , Humanos , Modelos Biológicos , Modelos Genéticos , Proteína 1 Homóloga a MutL , Transdução de Sinais , Proteína Tumoral p73 , Proteína Supressora de Tumor p53/metabolismo
2.
Environ Mol Mutagen ; 44(4): 249-64, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15468331

RESUMO

Deficiencies in DNA mismatch repair (MMR) have been found in both hereditary cancer (i.e., hereditary nonpolyposis colorectal cancer) and sporadic cancers of various tissues. In addition to its primary roles in the correction of DNA replication errors and suppression of recombination, research in the last 10 years has shown that MMR is involved in many other processes, such as interaction with other DNA repair pathways, cell cycle checkpoint regulation, and apoptosis. Indeed, a cell's MMR status can influence its response to a wide variety of chemotherapeutic agents, such as temozolomide (and many other methylating agents), 6-thioguanine, cisplatin, ionizing radiation, etoposide, and 5-fluorouracil. For this reason, identification of a tumor's MMR deficiency (as indicated by the presence of microsatellite instability) is being utilized more and more as a prognostic indicator in the clinic. Here, we describe the basic mechanisms of MMR and apoptosis and investigate the literature examining the influence of MMR status on the apoptotic response following treatment with various therapeutic agents. Furthermore, using isogenic MMR-deficient (HCT116) and MMR-proficient (HCT116 3-6) cells, we demonstrate that there is no enhanced apoptosis in MMR-proficient cells following treatment with 5-fluoro-2'-deoxyuridine. In fact, apoptosis accounts for only a small portion of the induced cell death response.


Assuntos
Antineoplásicos/farmacologia , Apoptose/fisiologia , Pareamento Incorreto de Bases/fisiologia , Camptotecina/análogos & derivados , Reparo do DNA/fisiologia , Floxuridina/farmacologia , Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Camptotecina/farmacologia , Cisplatino/farmacologia , Adutos de DNA/metabolismo , Fluoruracila/farmacologia , Nucleotídeos de Guanina/farmacologia , Células HCT116 , Humanos , Irinotecano , Radiação Ionizante , Tionucleotídeos/farmacologia
3.
Oncogene ; 22(47): 7376-88, 2003 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-14576845

RESUMO

The phenomenon of damage tolerance, whereby cells incur DNA lesions that are nonlethal, largely ignored, but highly mutagenic, appears to play a key role in carcinogenesis. Typically, these lesions are generated by alkylation of DNA or incorporation of base analogues. This tolerance is usually a result of the loss of specific DNA repair processes, most often DNA mismatch repair (MMR). The availability of genetically matched MMR-deficient and -corrected cell systems allows dissection of the consequences of this unrepaired damage in carcinogenesis as well as the elucidation of cell cycle checkpoint responses and cell death consequences. Recent data indicate that MMR plays an important role in detecting damage caused by fluorinated pyrimidines (FPs) and represents a repair system that is probably not the primary system for detecting damage caused by these agents, but may be an important system for correcting key mutagenic lesions that could initiate carcinogenesis. In fact, clinical studies have shown that there is no benefit of FP-based adjuvant chemotherapy in colon cancer patients exhibiting microsatellite instability, a hallmark of MMR deficiency. MMR-mediated damage tolerance and futile cycle repair processes are discussed, as well as possible strategies using FPs to exploit these systems for improved anticancer therapy.


Assuntos
Pareamento Incorreto de Bases/genética , Dano ao DNA/efeitos dos fármacos , Reparo do DNA , Pirimidinas/farmacologia , Animais , Citidina/análogos & derivados , Citidina/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Pirimidinas/metabolismo , Processamento Pós-Transcricional do RNA/efeitos dos fármacos
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