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1.
Sci Transl Med ; 10(427)2018 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-29437148

RESUMO

The gastrointestinal (GI) epithelium is the fastest renewing adult tissue and is maintained by tissue-specific stem cells. Treatment-induced GI side effects are a major dose-limiting factor for chemotherapy and abdominal radiotherapy and can decrease the quality of life in cancer patients and survivors. p53 is a key regulator of the DNA damage response, and its activation results in stimulus- and cell type-specific outcomes via distinct effectors. We demonstrate that p53-dependent PUMA induction mediates chemotherapy-induced intestinal injury in mice. Genetic ablation of Puma, but not of p53, protects against chemotherapy-induced lethal GI injury. Blocking chemotherapy-induced loss of LGR5+ stem cells by Puma KO or a small-molecule PUMA inhibitor (PUMAi) prevents perturbation of the stem cell niche, rapid activation of WNT and NOTCH signaling, and stem cell exhaustion during repeated exposures. PUMAi also protects human and mouse colonic organoids against chemotherapy-induced apoptosis and damage but does not protect cancer cells in vitro or in vivo. Therefore, targeting PUMA is a promising strategy for normal intestinal chemoprotection because it selectively blocks p53-dependent stem cell loss but leaves p53-dependent protective effects intact.


Assuntos
Células-Tronco/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Morte Celular/genética , Morte Celular/fisiologia , Intestinos/citologia , Irinotecano/efeitos adversos , Camundongos , Camundongos Knockout , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
2.
Proc Natl Acad Sci U S A ; 111(46): 16520-5, 2014 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-25368155

RESUMO

Colorectal tumorigenesis is driven by genetic alterations in the adenomatous polyposis coli (APC) tumor suppressor pathway and effectively inhibited by nonsteroidal antiinflammatory drugs (NSAIDs). However, how NSAIDs prevent colorectal tumorigenesis has remained obscure. We found that the extrinsic apoptotic pathway and the BH3 interacting-domain death agonist (BID) are activated in adenomas from NSAID-treated patients. Loss of BID abolishes NSAID-mediated tumor suppression, survival benefit, and apoptosis in tumor-initiating stem cells in APC(Min/+) mice. BID-mediated cross-talk between the extrinsic and intrinsic apoptotic pathways is responsible for selective killing of neoplastic cells by NSAIDs. We further demonstrate that NSAIDs induce death receptor signaling in both cancer and normal cells, but only activate BID in cells with APC deficiency and ensuing c-Myc activation. Our results suggest that NSAIDs suppress intestinal tumorigenesis through BID-mediated synthetic lethality triggered by death receptor signaling and gatekeeper mutations, and provide a rationale for developing more effective cancer prevention strategies and agents.


Assuntos
Polipose Adenomatosa do Colo/prevenção & controle , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/fisiologia , Genes APC , Polipose Adenomatosa do Colo/patologia , Animais , Proteínas Reguladoras de Apoptose/fisiologia , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/antagonistas & inibidores , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/deficiência , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/genética , Caspases/fisiologia , Linhagem Celular Tumoral , Colo/patologia , Regulação Neoplásica da Expressão Gênica , Genes myc , Humanos , Indometacina/farmacologia , Intestino Delgado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mitocôndrias/metabolismo , Especificidade de Órgãos , Pirazóis/farmacologia , RNA Interferente Pequeno/farmacologia , Receptores de Morte Celular/fisiologia , Células-Tronco/metabolismo , Células-Tronco/patologia , Sulfonamidas/farmacologia , Sulindaco/farmacologia
3.
J Clin Invest ; 121(5): 1722-32, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21490394

RESUMO

Intestinal epithelial cell (IEC) apoptosis contributes to the development of ulcerative colitis (UC), an inflammatory bowel disease (IBD) that affects the colon and rectum. Therapies that target the inflammatory cytokine TNF have been found to inhibit IEC apoptosis in patients with IBD, although the mechanism of IEC apoptosis remains unclear. We therefore investigated the role of p53-upregulated modulator of apoptosis (PUMA), a p53 target and proapoptotic BH3-only protein, in colitis and IEC apoptosis, using patient samples and mouse models of UC. In UC patient samples, PUMA expression was elevated in colitis tissues relative to that in uninvolved tissues, and the degree of elevation of PUMA expression correlated with the severity of colitis and the degree of apoptosis induction. In mice, PUMA was markedly induced in colonic epithelial cells following induction of colitis by either dextran sulfate sodium salt (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS). The induction of PUMA was p53-independent but required NF-κB. Absence of PUMA, but neither absence of p53 nor that of another BH3-only protein (Bid), relieved DSS- and TNBS-induced colitis and inhibited IEC apoptosis. Furthermore, treating mice with infliximab (Remicade), a clinically used TNF-specific antibody, suppressed DSS- and TNBS-induced PUMA expression and colitis. These results indicate that PUMA induction contributes to the pathogenesis of colitis by promoting IEC apoptosis and suggest that PUMA inhibition may be an effective strategy to promote mucosal healing in patients with UC.


Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Apoptose , Colite Ulcerativa/metabolismo , Células Epiteliais/metabolismo , Mucosa Intestinal/metabolismo , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Adolescente , Adulto , Idoso , Animais , Anticorpos Monoclonais/farmacologia , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Criança , Sulfato de Dextrana/farmacologia , Feminino , Humanos , Infliximab , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Ácido Trinitrobenzenossulfônico/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Proteína Supressora de Tumor p53/metabolismo
4.
J Neurosci ; 30(30): 10135-43, 2010 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-20668197

RESUMO

Nonspecific cognitive impairments are one of the many manifestations of neurofibromatosis type 1 (NF1). A learning phenotype is also present in Drosophila melanogaster that lack a functional neurofibromin gene (nf1). Multiple studies have indicated that Nf1-dependent learning in Drosophila involves the cAMP pathway, including the demonstration of a genetic interaction between Nf1 and the rutabaga-encoded adenylyl cyclase (Rut-AC). Olfactory classical conditioning experiments have previously demonstrated a requirement for Rut-AC activity and downstream cAMP pathway signaling in neurons of the mushroom bodies. However, Nf1 expression in adult mushroom body neurons has not been observed. Here, we address this discrepancy by demonstrating (1) that Rut-AC is required for the acquisition and stability of olfactory memories, whereas Nf1 is only required for acquisition, (2) that expression of nf1 RNA can be detected in the cell bodies of mushroom body neurons, and (3) that expression of an nf1 transgene only in the alpha/beta subset of mushroom body neurons is sufficient to restore both protein synthesis-independent and protein synthesis-dependent memory. Our observations indicate that memory-related functions of Rut-AC are both Nf1-dependent and -independent, that Nf1 mediates the formation of two distinct memory components within a single neuron population, and that our understanding of Nf1 function in memory processes may be dissected from its role in other brain functions by specifically studying the alpha/beta mushroom body neurons.


Assuntos
Encéfalo/citologia , Condicionamento Clássico/fisiologia , Memória/fisiologia , Neurofibromatose 1/metabolismo , Neurônios/fisiologia , Adenilil Ciclases/genética , Animais , Animais Geneticamente Modificados , Comportamento Animal , Encéfalo/crescimento & desenvolvimento , Drosophila , Proteínas de Drosophila/genética , Feminino , Regulação da Expressão Gênica/genética , Masculino , Corpos Pedunculados/citologia , Corpos Pedunculados/crescimento & desenvolvimento , Mutação/genética , Neurofibromatose 1/genética , Neurônios/classificação , Condutos Olfatórios/fisiologia , Transdução de Sinais/genética , Olfato/fisiologia , Fatores de Tempo
5.
J Neurosci ; 29(5): 1573-9, 2009 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-19193904

RESUMO

Assigning a gene's function to specific pathways used for classical conditioning, such as conditioned stimulus (CS) and unconditioned stimulus (US) pathway, is important for understanding the fundamental molecular and cellular mechanisms underlying memory formation. Prior studies have shown that the GABA receptor RDL inhibits aversive olfactory learning via its role in the Drosophila mushroom bodies (MBs). Here, we describe the results of further behavioral tests to further define the pathway involvement of RDL. The expression level of Rdl in the MBs influenced both appetitive and aversive olfactory learning, suggesting that it functions by suppressing a common pathway used for both forms of olfactory learning. Rdl knock down failed to enhance learning in animals carrying mutations in genes of the cAMP signaling pathway, such as rutabaga and NF1, suggesting that RDL works up stream of these functions in CS/US integration. Finally, knocking down Rdl or over expressing the dopamine receptor dDA1 in the MBs enhanced olfactory learning, but no significant additional enhancement was detected with both manipulations. The combined data suggest that RDL suppresses olfactory learning via CS pathway involvement.


Assuntos
Condicionamento Clássico/fisiologia , Proteínas de Drosophila/fisiologia , Aprendizagem/fisiologia , Receptores de GABA-A/fisiologia , Olfato/fisiologia , Animais , Aprendizagem por Associação/fisiologia , Drosophila , Proteínas de Drosophila/genética , Técnicas de Silenciamento de Genes , Receptores de GABA-A/genética , Olfato/genética
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