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1.
J Exp Med ; 220(3)2023 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-36719686

RESUMO

Pharmacological inhibition of KRAS>RAF>MEK1/2>ERK1/2 signaling has provided no clinical benefit to patients with pancreatic ductal adenocarcinoma (PDAC). Interestingly, combined inhibition of MEK1/2 (with trametinib [T]) plus autophagy (with chloroquine [CQ] or hydroxychloroquine [HCQ]) demonstrated striking anti-tumor effects in preclinical models and in a patient (Patient 1). However, not all patients respond to the T/HCQ regimen, and Patient 1 eventually developed resistant disease. Here we report that primary or acquired resistance is associated with focal DNA copy number gains encompassing c-MYC. Furthermore, ectopic expression of c-MYC in PDAC cell lines rendered them T/HCQ resistant. Interestingly, a CDK4/6 inhibitor, palbociclib (P), also induced autophagy and overrode c-MYC-mediated T/HCQ resistance, such that P/HCQ promoted regression of T/HCQ-resistant PDAC tumors with elevated c-MYC expression. Finally, P/HCQ treatment of Patient 1 resulted in a biochemical disease response. These data suggest that elevated c-MYC expression is both a marker and a mediator of T/HCQ resistance, which may be overcome by the use of P/HCQ.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Quinase 4 Dependente de Ciclina/uso terapêutico , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Lisossomos/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas
2.
Annu Rev Cell Dev Biol ; 34: 311-332, 2018 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-30089222

RESUMO

Balancing cell death and survival is essential for normal development and homeostasis and for preventing diseases, especially cancer. Conventional cell death pathways include apoptosis, a form of programmed cell death controlled by a well-defined biochemical pathway, and necrosis, the lysis of acutely injured cells. New types of regulated cell death include necroptosis, pyroptosis, ferroptosis, phagoptosis, and entosis. Autophagy can promote survival or can cause death. Newly described processes of anastasis and resuscitation show that, remarkably, cells can recover from the brink of apoptosis or necroptosis. Important new work shows that epithelia achieve homeostasis by extruding excess cells, which then die by anoikis due to loss of survival signals. This mechanically regulated process both maintains barrier function as cells die and matches rates of proliferation and death. In this review, we describe these unconventional ways in which cells have evolved to die or survive, as well as the contributions that these processes make to homeostasis and cancer.


Assuntos
Apoptose/genética , Autofagia/genética , Necrose/genética , Neoplasias/genética , Anoikis/genética , Proliferação de Células/genética , Entose/genética , Homeostase/genética , Humanos , Piroptose/genética , Transdução de Sinais/genética
3.
Semin Cell Dev Biol ; 67: 132-140, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27212253

RESUMO

To remove dying or unwanted cells from an epithelium while preserving the barrier function of the layer, epithelia use a unique process called cell extrusion. To extrude, the cell fated to die emits the lipid Sphingosine 1 Phosphate (S1P), which binds the G-protein-coupled receptor Sphingosine 1 Phosphate receptor 2 (S1P2) in the neighboring cells that activates Rho-mediated contraction of an actomyosin ring circumferentially and basally. This contraction acts to squeeze the cell out apically while drawing together neighboring cells and preventing any gaps to the epithelial barrier. Epithelia can extrude out cells targeted to die by apoptotic stimuli to repair the barrier in the face of death or extrude live cells to promote cell death when epithelial cells become too crowded. Indeed, because epithelial cells naturally turn over by cell death and division at some of the highest rates in the body, epithelia depend on crowding-induced live cell extrusion to preserve constant cell numbers. If extrusion is defective, epithelial cells rapidly lose contact inhibition and form masses. Additionally, because epithelia act as the first line of defense in innate immunity, preservation of this barrier is critical for preventing pathogens from invading the body. Given its role in controlling constant cell numbers and maintaining barrier function, a number of different pathologies can result when extrusion is disrupted. Here, we review mechanisms and signaling pathways that control epithelial extrusion and discuss how defects in these mechanisms can lead to multiple diseases. We also discuss tactics pathogens have devised to hijack the extrusion process to infect and colonize epithelia.


Assuntos
Proteína da Polipose Adenomatosa do Colo/metabolismo , Polipose Adenomatosa do Colo/metabolismo , Células Epiteliais/metabolismo , Lisofosfolipídeos/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Transdução de Sinais , Esfingosina/análogos & derivados , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Apoptose , Movimento Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células Epiteliais/patologia , Regulação da Expressão Gênica , Humanos , Listeria monocytogenes/patogenicidade , Listeria monocytogenes/fisiologia , Proteína Inibidora de Apoptose Neuronal/genética , Proteína Inibidora de Apoptose Neuronal/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptores de Lisoesfingolipídeo/genética , Salmonella typhimurium/patogenicidade , Salmonella typhimurium/fisiologia , Esfingosina/metabolismo , Receptores de Esfingosina-1-Fosfato , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
4.
RNA Dis ; 3(1)2016.
Artigo em Inglês | MEDLINE | ID: mdl-27088130

RESUMO

Transcription elongation is a critical regulatory step in the gene expression cycle. One key regulator of the switch between transcription initiation and elongation is the P-TEFb kinase, which phosphorylates RNA polymerase II (Pol II) and several negative elongation factors to relieve the elongation block at paused promoters to facilitate productive elongation. Here, we highlight recent findings signifying the role of the PPM1G/PP2Cγ phosphatase in activating and maintaining the active transcription elongation state by regulating the availability of P-TEFb and blocking its assembly into the catalytic inactive 7SK small nuclear ribonucleoprotein (snRNP) complex.

5.
Mol Cell Biol ; 35(22): 3810-28, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26324325

RESUMO

Transcription elongation programs are vital for the precise regulation of several biological processes. One key regulator of such programs is the P-TEFb kinase, which phosphorylates RNA polymerase II (Pol II) once released from the inhibitory 7SK small nuclear ribonucleoprotein (snRNP) complex. Although mechanisms of P-TEFb release from the snRNP are becoming clearer, how P-TEFb remains in the 7SK-unbound state to sustain transcription elongation programs remains unknown. Here we report that the PPM1G phosphatase (inducibly recruited by nuclear factor κB [NF-κB] to target promoters) directly binds 7SK RNA and the kinase inhibitor Hexim1 once P-TEFb has been released from the 7SK snRNP. This dual binding activity of PPM1G blocks P-TEFb reassembly onto the snRNP to sustain NF-κB-mediated Pol II transcription in response to DNA damage. Notably, the PPM1G-7SK RNA interaction is direct, kinetically follows the recruitment of PPM1G to promoters to activate NF-κB transcription, and is reversible, since the complex disassembles before resolution of the program. Strikingly, we found that the ataxia telangiectasia mutated (ATM) kinase regulates the interaction between PPM1G and the 7SK snRNP through site-specific PPM1G phosphorylation. The precise and temporally regulated interaction of a cellular enzyme and a noncoding RNA provides a new paradigm for simultaneously controlling the activation and maintenance of inducible transcription elongation programs.


Assuntos
Fosfoproteínas Fosfatases/metabolismo , Fator B de Elongação Transcricional Positiva/metabolismo , RNA Nuclear Pequeno/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Ativação Transcricional , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Dano ao DNA , Células HEK293 , Células HeLa , Humanos , Modelos Moleculares , NF-kappa B/metabolismo , Conformação de Ácido Nucleico , Fosfoproteínas Fosfatases/química , Ligação Proteica , Proteína Fosfatase 2C , Estrutura Terciária de Proteína , RNA Polimerase II/metabolismo , RNA Nuclear Pequeno/química , Fatores de Transcrição
6.
Biochim Biophys Acta ; 1844(9): 1656-61, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24948475

RESUMO

The Cus system of Escherichia coli aids in protection of cells from high concentrations of Ag(I) and Cu(I). The histidine kinase CusS of the CusRS two-component system functions as a Ag(I)/Cu(I)-responsive sensor kinase and is essential for induction of the genes encoding the CusCFBA efflux pump. In this study, we have examined the molecular features of the sensor domain of CusS in order to understand how a metal-responsive histidine kinase senses specific metal ions. We find that the predicted periplasmic sensor domain of CusS directly interacts with Ag(I) ions and undergoes a conformational change upon metal binding. Metal binding also enhances the tendency of the domain to dimerize. These findings suggest a model for activation of the histidine kinase through metal binding events in the periplasmic sensor domain.


Assuntos
Proteínas de Escherichia coli/metabolismo , Escherichia coli/enzimologia , Periplasma/enzimologia , Proteínas Quinases/metabolismo , Prata/metabolismo , Cátions Monovalentes , Cobre/metabolismo , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Expressão Gênica , Histidina Quinase , Cinética , Periplasma/genética , Ligação Proteica , Proteínas Quinases/genética , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína
7.
Cell Rep ; 5(5): 1256-68, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24316072

RESUMO

The transition from transcription initiation into elongation is controlled by transcription factors, which recruit positive transcription elongation factor b (P-TEFb) to promoters to phosphorylate RNA polymerase II. A fraction of P-TEFb is recruited as part of the inhibitory 7SK small nuclear ribonucleoprotein particle (snRNP), which inactivates the kinase and prevents elongation. However, it is unclear how P-TEFb is captured from the promoter-bound 7SK snRNP to activate elongation. Here, we describe a mechanism by which transcription factors mediate the enzymatic release of P-TEFb from the 7SK snRNP at promoters to trigger activation in a gene-specific manner. We demonstrate that Tat recruits PPM1G/PP2Cγ to locally disassemble P-TEFb from the 7SK snRNP at the HIV promoter via dephosphorylation of the kinase T loop. Similar to Tat, nuclear factor (NF)-κB recruits PPM1G in a stimulus-dependent manner to activate elongation at inflammatory-responsive genes. Recruitment of PPM1G to promoter-assembled 7SK snRNP provides a paradigm for rapid gene activation through transcriptional pause release.


Assuntos
Fosfoproteínas Fosfatases/metabolismo , Fator B de Elongação Transcricional Positiva/metabolismo , Regiões Promotoras Genéticas , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Elongação da Transcrição Genética , Células HEK293 , Células HeLa , Humanos , NF-kappa B/metabolismo , Fosforilação , Fator B de Elongação Transcricional Positiva/química , Ligação Proteica , Proteína Fosfatase 2C , Estrutura Terciária de Proteína
8.
FEMS Microbiol Lett ; 330(1): 30-7, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22348296

RESUMO

Two-component systems are widely used by bacteria to mediate adaptive responses to a variety of environmental stimuli. The CusR/CusS two-component system in Escherichia coli induces expression of genes involved in metal efflux under conditions of elevated Cu(I) and Ag(I) concentrations. As seen in most prototypical two-component systems, signal recognition and transmission is expected to occur by ligand binding in the periplasmic sensor domain of the histidine kinase CusS. Although discussed in the extant literature, little experimental evidence is available to establish the role of CusS in metal homeostasis. In this study, we show that the cusS gene is required for Cu(I) and Ag(I) resistance in E. coli and that CusS is linked to the expression of the cusCFBA genes. These results show a metal-dependent mechanism of CusS activation and suggest an absolute requirement for CusS in Cu(I)- and Ag(I)-dependent upregulation of cusCFBA expression in E. coli.


Assuntos
Cobre/metabolismo , Proteínas de Escherichia coli/metabolismo , Escherichia coli/fisiologia , Regulação Bacteriana da Expressão Gênica , Proteínas de Membrana Transportadoras/biossíntese , Proteínas Quinases/metabolismo , Prata/metabolismo , Cobre/toxicidade , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Histidina Quinase , Proteínas Quinases/genética , Prata/toxicidade
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