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1.
Cell Rep ; 12(4): 610-21, 2015 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-26190111

RESUMO

Akt is frequently activated in human cancers. However, it is unknown whether systemic inhibition of a single Akt isoform could regress cancer progression in cancers that are not driven by Akt activation. We systemically deleted Akt1 after tumor onset in p53(-/-) mice, which develop tumors independently of Akt activation. Systemic Akt1 deletion regresses thymic lymphoma in p53(-/-) mice emulating p53 restoration. Furthermore, pharmacological inhibition of Akt selectively kills thymic lymphoma cells and not primary thymocytes. Mechanistically, Akt1 inhibition in p53(-/-) thymic lymphoma inhibits Skp2 expression and induces FasL, which is the primary cause of cell death. Skp2 exerts resistance to cell death by antagonizing the induction of FasL and reducing FAS expression, which is linked to cyclin D1 expression. The results established a paradigm whereby systemic Akt1 inhibition is sufficient to regress tumors that are not driven by Akt activation and a mechanism of cell survival by Skp2.


Assuntos
Longevidade , Linfoma/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Timócitos/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Apoptose , Linhagem Celular Tumoral , Proteína Ligante Fas/metabolismo , Humanos , Linfoma/patologia , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismo , Timócitos/patologia , Proteína Supressora de Tumor p53/metabolismo
2.
Cancer Cell ; 24(2): 213-228, 2013 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-23911236

RESUMO

Accelerated glucose metabolism is a common feature of cancer cells. Hexokinases catalyze the first committed step of glucose metabolism. Hexokinase 2 (HK2) is expressed at high level in cancer cells, but only in a limited number of normal adult tissues. Using Hk2 conditional knockout mice, we showed that HK2 is required for tumor initiation and maintenance in mouse models of KRas-driven lung cancer, and ErbB2-driven breast cancer, despite continued HK1 expression. Similarly, HK2 ablation inhibits the neoplastic phenotype of human lung and breast cancer cells in vitro and in vivo. Systemic Hk2 deletion is therapeutic in mice bearing lung tumors without adverse physiological consequences. Hk2 deletion in lung cancer cells suppressed glucose-derived ribonucleotides and impaired glutamine-derived carbon utilization in anaplerosis.


Assuntos
Neoplasias da Mama/enzimologia , Hexoquinase/metabolismo , Neoplasias Pulmonares/enzimologia , Animais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Glicólise , Hexoquinase/biossíntese , Hexoquinase/genética , Humanos , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Knockout , Transplante Heterólogo
3.
Dev Cell ; 18(4): 592-604, 2010 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-20412774

RESUMO

FoxO transcription factors and TORC1 are conserved downstream effectors of Akt. Here, we unraveled regulatory circuits underlying the interplay between Akt, FoxO, and mTOR. Activated FoxO1 inhibits mTORC1 by TSC2-dependent and TSC2-independent mechanisms. First, FoxO1 induces Sestrin3 (Sesn3) gene expression. Sesn3, in turn, inhibits mTORC1 activity in Tsc2-proficient cells. Second, FoxO1 elevates the expression of Rictor, leading to increased mTORC2 activity that consequently activates Akt. In Tsc2-deficient cells, the elevation of Rictor by FoxO increases mTORC2 assembly and activity at the expense of mTORC1, thereby activating Akt while inhibiting mTORC1. FoxO may act as a rheostat that maintains homeostatic balance between Akt and mTOR complexes' activities. In response to physiological stresses, FoxO maintains high Akt activity and low mTORC1 activity. Thus, under stress conditions, FoxO inhibits the anabolic activity of mTORC1, a major consumer of cellular energy, while activating Akt, which increases cellular energy metabolism, thereby maintaining cellular energy homeostasis.


Assuntos
Proteínas de Transporte/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Regulação Enzimológica da Expressão Gênica , Proteínas de Choque Térmico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologia , Animais , Sequência de Bases , Ativação Enzimática , Proteína Forkhead Box O3 , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Dados de Sequência Molecular , Complexos Multiproteicos , Proteínas , Proteína Companheira de mTOR Insensível à Rapamicina , Homologia de Sequência do Ácido Nucleico , Serina-Treonina Quinases TOR , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/metabolismo
4.
Mol Cell Biol ; 29(18): 5136-47, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19620286

RESUMO

The current concept is that Tsc-deficient cells are sensitized to apoptosis due to the inhibition of Akt activity by the negative feedback mechanism induced by the hyperactive mTORC1. Unexpectedly, however, we found that Tsc1/2-deficient cells exhibit increased resistance to serum deprivation-induced apoptosis. mTORC1 hyperactivity contributes to the apoptotic resistance of serum-deprived Tsc1/2-deficient cells in part by increasing the growth factor-independent expression of hexokinase II (HKII) and GLUT1. mTORC1-mediated increase in hypoxia-inducible factor 1alpha (HIF1alpha) abundance, which occurs in the absence of serum in normoxic Tsc2-deficient cells, contributes to these changes. Increased HIF1alpha abundance in these cells is attributed to both an increased level and the sustained translation of HIF1alpha mRNA. Sustained glycogen synthase kinase 3beta inhibition and Mcl-1 expression also contribute to the apoptotic resistance of Tsc2-deficient cells to serum deprivation. The inhibition of mTORC1 activity by either rapamycin or Raptor knockdown cannot resensitize these cells to serum deprivation-induced apoptosis because of elevated Akt activity that is an indirect consequence of mTORC1 inhibition. However, the increased HIF1alpha abundance and the maintenance of Mcl-1 protein expression in serum-deprived Tsc2(-/)(-) cells are dependent largely on the hyperactive eIF4E in these cells. Consistently, the reduction of eIF4E levels abrogates the resistance of Tsc2(-/)(-) cells to serum deprivation-induced apoptosis.


Assuntos
Apoptose , Transportador de Glucose Tipo 1/metabolismo , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Hexoquinase/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Soro/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apoptose/efeitos dos fármacos , Embrião de Mamíferos/citologia , Ativação Enzimática/efeitos dos fármacos , Fator de Iniciação 4E em Eucariotos/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Glicogênio Sintase Quinase 3 beta , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Complexos Multiproteicos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Fosforilação/efeitos dos fármacos , Proteínas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirolimo/farmacologia , Serina-Treonina Quinases TOR , Fatores de Transcrição/antagonistas & inibidores , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/metabolismo , Proteína de Morte Celular Associada a bcl/metabolismo
5.
Dev Cell ; 12(4): 487-502, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17419990

RESUMO

The regulatory circuits that control the activities of the two distinct target of rapamycin (TOR) complexes, TORC1 and TORC2, and of Akt have been a focus of intense research in recent years. It has become increasingly evident that these regulatory circuits control some of the most fundamental aspects of metabolism, cell growth, proliferation, survival, and differentiation at both the cellular and organismal levels. As such, they also play a pivotal role in the genesis of diseases including cancer, diabetes, aging, and degenerative diseases. This review highlights recent developments aimed at deciphering the interplay between Akt and mTORCs as well as their role in embryonic development and in cancer.


Assuntos
Regulação da Expressão Gênica , Neoplasias/metabolismo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição/metabolismo , Animais , Sequência Conservada , Evolução Molecular , Desenvolvimento Fetal , Humanos , Camundongos , Camundongos Knockout , Modelos Biológicos , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Transativadores/metabolismo , Fatores de Transcrição/genética
6.
Cancer Cell ; 10(4): 269-80, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17045205

RESUMO

Akt contributes to tumorigenesis by inhibiting apoptosis. Here we establish that Akt is required for normal cell proliferation and susceptibility to oncogenesis independently of its antiapoptotic activity. Partial ablation of Akt activity by deleting Akt1 inhibits cell proliferation and oncogenesis. These effects are compounded by deleting both Akt1 and Akt2. In vivo, Akt1 null mice are resistant to MMTV-v-H-Ras-induced tumors and to skin carcinogenesis. Thus, partial ablation of Akt activity is sufficient to suppress tumorigenesis in vitro and in vivo. The effect of Akt deficiency on cell proliferation and oncogenesis is p53 independent but mTORC1 dependent. Surprisingly, upon mTORC1 hyperactivation, the reduction in Akt activity does not impair cell proliferation and susceptibility to oncogenic transformation; thus, Akt may mediate these processes exclusively via mTORC1.


Assuntos
Proliferação de Células , Neoplasias/etiologia , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/deficiência , Transativadores/metabolismo , Animais , Linhagem Celular Transformada , Transformação Celular Viral , Cruzamentos Genéticos , Embrião de Mamíferos , Fibroblastos/metabolismo , Cinética , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Complexos Multiproteicos , Neoplasias/patologia , Proteínas Quinases/genética , Proteínas , Proteínas Proto-Oncogênicas c-akt/genética , Retroviridae/genética , Serina-Treonina Quinases TOR , Transativadores/genética , Fatores de Transcrição , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
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