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1.
Proc Natl Acad Sci U S A ; 106(11): 4390-5, 2009 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-19251665

RESUMO

The expression of ASPP2 (53BP2L), a proapoptotic member of a family of p53-binding proteins, is frequently suppressed in many human cancers. Accumulating evidence suggests that ASPP2 inhibits tumor growth; however, the mechanisms by which ASPP2 suppresses tumor formation remain to be clarified. To study this, we targeted the ASPP2 allele in a mouse by replacing exons 10-17 with a neoR gene. ASPP2(-/-) mice were not viable because of an early embryonic lethal event. Although ASPP2(+/-) mice appeared developmentally normal, they displayed an increased incidence of a variety of spontaneous tumors as they aged. Moreover, gamma-irradiated 6-week-old ASPP2(+/-) mice developed an increased incidence of high-grade T cell lymphomas of thymic origin compared with ASPP2(+/+) mice. Primary thymocytes derived from ASPP2(+/-) mice exhibited an attenuated apoptotic response to gamma-irradiation compared with ASPP2(+/+) thymocytes. Additionally, ASPP2(+/-) primary mouse embryonic fibroblasts demonstrated a defective G(0)/G(1) cell cycle checkpoint after gamma-irradiation. Our results demonstrate that ASPP2 is a haploinsufficient tumor suppressor and, importantly, open new avenues for investigation into the mechanisms by which disruption of ASPP2 pathways could play a role in tumorigenesis and response to therapy.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Proteínas Supressoras de Tumor/genética , Animais , Apoptose/efeitos da radiação , Ciclo Celular/efeitos da radiação , Raios gama , Predisposição Genética para Doença , Heterozigoto , Linfoma de Células T/etiologia , Linfoma de Células T/genética , Camundongos , Camundongos Mutantes , Neoplasias/etiologia , Neoplasias/genética , Timo
2.
Cell Cycle ; 8(18): 2871-6, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19657229

RESUMO

Apoptosis Stimulating Protein of p53-2, ASPP2, aka 53BP2L, (encoded by TP53BP2) is a pro-apoptotic member of a family of p53 binding proteins. ASPP2 expression is frequently suppressed in human cancers and numerous studies have consistently demonstrated that ASPP2 inhibits cell growth as well as stimulates apoptosis-at least in part through a p53-mediated pathway. Two independent mouse models have shown that ASPP2 is a haplo-insufficient tumor suppressor and underscore the importance of the role of ASPP2 in human cancer. However, mounting evidence suggests that the mechanism(s) of action for ASPP2 are complex and likely extend beyond stimulation of apoptotic programs. Data highlighting this expanding spectrum of potential ASPP2-mediated pathways is summarized along with new results from recent in vivo models suggesting new avenues for investigation.


Assuntos
Perfilação da Expressão Gênica , Proteínas Supressoras de Tumor/genética , Animais , Apoptose , Ciclo Celular , Camundongos , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/deficiência
3.
Cell Cycle ; 8(16): 2621-30, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19625780

RESUMO

AML remains a difficult disease to treat. Despite response to induction chemotherapy, most patients ultimately relapse. Further, among elderly patients, aggressive therapy options are often limited due to other medical conditions and decreased tolerance of these patients to conventional chemotherapy. Internal tandem duplications (ITD) of the FLT3 juxtamembrane domain occur in 20-30% of AML patients and predict poor outcome. First clinical data with the FLT3 inhibitor tandutinib demonstrated antileukemic activity in approximately half of the patients--predominantly with FLT3 ITD positive AML. But the data also show that optimal use of tandutinib will require combination therapy with cytotoxic agents. Notably, single agent tandutinib has not been associated with myelosuppression, mucositis or cardiac toxicity--the dose limiting toxicities of AML chemotherapy. We determined the feasibility of combining tandutinib with the standard "3 + 7" induction regimen in AML and show that, in contrast to other structurally unrelated FLT3 inhibitors recently evaluated in clinical trials, the use of tandutinib displayed application sequence independent synergistic antileukemic effects in combination with cytarabine and daunorubicin. Strong synergistic antiproliferative and proapoptotic effects were thereby predominantly seen on FLT3 ITD positive blasts. Further we demonstrate, that addition of tandutinib may allow dose reduction of chemotherapy without loss of overall antileukemic activity--resulting in a potential decrease of side effects. This approach might be an interesting novel strategy especially in the treatment of elderly/comorbid patients. Our data provide a rationale for combining tandutinib with induction chemotherapy in intensified as well as in dose reduction protocols for FLT3 ITD positive AML.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Citarabina/farmacologia , Daunorrubicina/farmacologia , Piperazinas/farmacologia , Quinazolinas/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Citometria de Fluxo , Células HL-60 , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico
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