Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Clin Immunol ; 258: 109874, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38113962

RESUMO

Sle1 and Faslpr are two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus. To evaluate the dosage effects of Faslpr in determining cellular and serological phenotypes associated with lupus, we developed a new C57BL/6 (B6) congenic lupus strain, B6.Sle1/Sle1.Faslpr/+ (Sle1homo.lprhet) and compared it with B6.Faslpr/lpr (lprhomo), B6.Sle1/Sle1 (Sle1homo), and B6.Sle1/Sle1.Faslpr/lpr (Sle1homo.lprhomo) strains. Whereas Sle1homo.lprhomo mice exhibited profound lymphoproliferation and early mortality, Sle1homo.lprhet mice had a lifespan comparable to B6 mice, with no evidence of splenomegaly or lymphadenopathy. Compared to B6 monogenic lupus strains, Sle1homo.lprhet mice exhibited significantly elevated serum ANA antibodies and increased proteinuria. Additionally, Sle1homo.lprhet T cells had an increased propensity to differentiate into Th1 cells. Gene dose effects of Faslpr were noted in upregulating serum IL-1⍺, IL-2, and IL-27. Taken together, Sle1homo.lprhet strain is a new C57BL/6-based model of lupus, ideal for genetic studies, autoantibody repertoire investigation, and for exploring Th1 effector cell skewing without early-age lymphoproliferative autoimmunity.


Assuntos
Lúpus Eritematoso Sistêmico , Camundongos , Animais , Camundongos Endogâmicos C57BL , Lúpus Eritematoso Sistêmico/genética , Autoimunidade , Diferenciação Celular , Dosagem de Genes , Camundongos Endogâmicos MRL lpr
2.
J Natl Compr Canc Netw ; 22(5)2024 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-38190801

RESUMO

Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for many cancer types. The clinical use of ICIs is increasing rapidly, including in combinations associated with increased risk of toxicities, termed "immune-related adverse events" (irAEs). Therefore, MD Anderson Cancer Center (MDACC) in Houston, Texas has proactively responded by developing a priority endeavor known as the Immuno-Oncology Toxicity (IOTOX) initiative. This strategic initiative aims to facilitate the seamless integration of key domains: (1) standardized clinical practice and innovative decision toolsets; (2) patient and provider education; and (3) a comprehensive clinical and translational research platform. The ultimate goal of this initiative is to develop and disseminate clinical best practices and biologic insights into irAEs to improve outcomes of patients with irAEs at MDACC and in the wider oncology community.


Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/terapia , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Texas , Imunoterapia/métodos , Imunoterapia/efeitos adversos
3.
BMC Urol ; 17(1): 26, 2017 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-28381270

RESUMO

BACKGROUND: Ureteral herniations are a rare occurrence, generally found incidentally on cross sectional imaging or during surgical intervention for unrelated processes. Several locations of ureteral herniations can occur including the inguinal, femoral, sciatic, obturator, and thoracic regions. While few reports of ureteral hernias are reported in the literature overall, the vast majority of those reported are inguinoscrotal herniations found during evaluation and treatment of inguinal hernias. Pelvic outlet ureteral herniations intrinsically are more common secondary to their dependent locations. Intrathoracic ureteral herniations through diaphragmatic defects are an exceptionally rare subset of ureteral herniations and have only been described sparingly. Fewer than ten case reports of diaphramatic ureteral herniations have been reported and none have described both cystoscopic management and open reconstruction. CASE PRESENTATION: We report the case of a 81 year old female with flank pain who was found to have idiopathic diaphragmatic hernia with incarcerated proximal ureter. She had no prior injury or surgery that explained her clinical presentation. She was initially observed and then managed conservatively with ureteral stent exchanges. Ultimately she underwent open surgical repair of her diaphragmatic hernia, reduction, resection and anastomosis of redundant proximal incarcerated ureteral segment, and nephropexy for a hypermobile right renal unit. This case report illustrates the pre- and post-operative imaging studies of a very rare intrathoracic ureteral herniation as well as surgical approach to repair. CONCLUSION: A herniated ureter is a potential source of serious renal and ureteral complications. The thoracic herniation of ureter is the rarest of the ureteral herniations. When discovered, they should be managed to preserve renal function and prevent strangulation of the affected segment of ureter. This case report documents the treatment of a thoracic ureteral herniation with observation, conservative endoscopic management, and finally open surgical reconstruction.


Assuntos
Hérnia Diafragmática/cirurgia , Ureter/cirurgia , Doenças Ureterais/cirurgia , Idoso de 80 Anos ou mais , Endoscopia , Feminino , Hérnia Diafragmática/complicações , Hérnia Diafragmática/diagnóstico por imagem , Humanos , Tomografia Computadorizada por Raios X , Ureter/diagnóstico por imagem , Doenças Ureterais/diagnóstico por imagem , Obstrução Ureteral/diagnóstico por imagem , Obstrução Ureteral/etiologia
4.
Curr Diab Rep ; 16(5): 45, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27053072

RESUMO

Diabetes is increasing in prevalence and is the leading cause of end-stage renal disease in the United States. Diabetic kidney disease is considered a proteinuric glomerular disease. Although the glomerulus is composed of various cell types, research suggests that podocytes are critical to overall glomerular health. Podocyte injury has been identified as a pivotal event resulting in proteinuric kidney disease, glomerulosclerosis, and loss of renal function. Thus, understanding the signaling mechanisms that trigger podocyte injury in diabetic kidney disease might allow for the development of targeted therapeutics to prevent or ameliorate progression to end-stage renal failure. This review focuses on the role of podocytes in diabetic kidney disease.


Assuntos
Nefropatias Diabéticas/metabolismo , Podócitos/metabolismo , Adaptação Fisiológica , Animais , Progressão da Doença , Humanos , Falência Renal Crônica/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo
5.
Clin Kidney J ; 17(5): sfae127, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38803394

RESUMO

Immune checkpoint inhibitor (ICI)-associated immune nephritis or acute interstitial nephritis (AIN) is one of the rare but known complication of ICI therapy. Guidelines recommend treatment of ICI-associated AIN with steroids, then TNF-alpha inhibitor infliximab. However, some cases are refractory to these therapies, potentially due to insufficient cytokine blockade. This is the first case where a 65-year-old female with metastatic lung adenocarcinoma, requiring high maintenance doses of steroids for immune nephritis was treated with tofacitinib, an oral Janus kinase (JAK) inhibitor. Tofacitinib enabled successful steroid tapering and might be a therapy option for refractory immune nephritis.

6.
Leuk Res Rep ; 20: 100377, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37457553

RESUMO

Membranous nephropathy (MN) is an uncommon renal presentation in patients with chronic lymphocytic leukemia (CLL), and as such, there is no standard therapy for these patients. A few cases of MN in CLL have been described with varying success in MN treatment involving alkylating agents and fludarabine. Here we report the first case of MN in a patient with CLL treated with ibrutinib with complete renal response. This presentation underlines the importance of recognizing rare glomerular diseases that may occur with CLL and offers a new therapeutic avenue to the treatment of CLL-associated MN.

7.
JCI Insight ; 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36472921

RESUMO

Tertiary lymphoid structures (TLSs) are associated with anti-tumor response following immune checkpoint inhibitor (ICI) therapy, but a commensurate observation of TLS is absent for immune related adverse events (irAEs) i.e. acute interstitial nephritis (AIN). We hypothesized that TLS-associated inflammatory gene signatures are present in AIN and performed NanoString-based gene expression and multiplex 12-chemokine profiling on paired kidney tissue, urine and plasma specimens of 36 participants who developed acute kidney injury (AKI) on ICI therapy: AIN (18), acute tubular necrosis (9), or HTN nephrosclerosis (9). Increased T and B cell scores, a Th1-CD8+ T cell axis accompanied by interferon-g and TNF superfamily signatures were detected in the ICI-AIN group. TLS signatures were significantly increased in AIN cases and supported by histopathological identification. Furthermore, urinary TLS signature scores correlated with ICI-AIN diagnosis but not paired plasma. Urinary CXCL9 correlated best to tissue CXCL9 expression (rho 0.75, p < 0.001) and the ability to discriminate AIN vs. non-AIN (AUC 0.781, p-value 0.003). For the first time, we report the presence of TLS signatures in irAEs, define distinctive immune signatures, identify chemokine markers distinguishing ICI-AIN from common AKI etiologies and demonstrate that urine chemokine markers may be used as a surrogate for ICI-AIN diagnoses.

8.
Front Immunol ; 13: 898811, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35967405

RESUMO

Background: Diagnosing immune checkpoint inhibitor (ICI)-associated nephritis can be challenging since it is a rare complication of therapy, associated with a spectrum of immune-mediated pathologies, and can present months after ICI therapy discontinuation (i.e., late-onset). ICIs are increasingly administered in combination with other cancer therapies with associated nephrotoxicity, further obfuscating the diagnosis of ICI-associated nephritis. In this report, we describe the first suspected case of late-onset ICI-associated membranous nephropathy (MN) in a patient with metastatic clear cell renal cell carcinoma (RCC) who had discontinued ICI therapy 6 months prior to presentation. Prompt recognition of the suspected late-onset immune-related adverse event (irAE) resulted in the successful treatment of MN and continuation of RCC therapy. Case presentation: A 57-year-old man with metastatic clear cell RCC was responsive to third-line RCC therapy with lenvatinib (oral TKI) and everolimus (oral mTOR inhibitor) when he presented with nephrotic range proteinuria and acute kidney injury (AKI). His kidney biopsy revealed probable secondary MN with subendothelial and mesangial immune complex deposits and negative staining for both phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A). While a diagnosis of paraneoplastic MN could not be excluded, the patient was responding to cancer therapy and had tumor regression. However, 6 months prior to presentation, the patient had received pembrolizumab, an ICI, with his first-line RCC treatment. Due to concern that the patient may be presenting with late-onset ICI-associated MN, he was effectively treated with rituximab, which allowed for his continued RCC therapy. Conclusion: This report highlights the first case of suspected late-onset ICI-associated MN and the increasing complexity of recognizing renal irAEs. With the growing indications for the use of ICIs in combination with other cancer therapies, recognizing the various presentations of ICI-immune nephritis can help guide patient management and treatment.


Assuntos
Carcinoma de Células Renais , Glomerulonefrite Membranosa , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/tratamento farmacológico , Glomerulonefrite Membranosa/induzido quimicamente , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Pessoa de Meia-Idade , Receptores da Fosfolipase A2
9.
Oncoimmunology ; 11(1): 2124678, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36185804

RESUMO

Acute kidney injury (AKI) occurs in ~20% of patients receiving immune checkpoint inhibitor (ICI) therapy; however, only 2-5% will develop ICI-mediated immune nephritis. Conventional tests are nonspecific in diagnosing disease pathology and invasive procedures (i.e. kidney biopsy) may not be feasible. In other autoimmune renal diseases, urinary immune cells correlated with the pathology or were predictive of disease activity. Corresponding evidence and analysis are absent for ICI-mediated immune nephritis. We report the first investigation analyzing immune cell profiles of matched kidney biopsies and urine of patients with ICI-AKI. We demonstrated the presence of urinary T cells in patients with immune nephritis by flow cytometry analysis. Clonotype analysis of T cell receptor (TCR) sequences confirmed enrichment of kidney TCRs in urine. As ICI therapies become standard of care for more cancers, noninvasively assessing urinary immune cells of ICI therapy recipients can facilitate clinical management and an opportunity to tailor ICI-nephritis treatment.


Assuntos
Injúria Renal Aguda , Nefrite , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Rim/patologia , Nefrite/induzido quimicamente , Nefrite/diagnóstico , Nefrite/tratamento farmacológico , Linfócitos T
10.
Oncoimmunology ; 10(1): 1877415, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33643693

RESUMO

Acute tubular interstitial nephritis (ATIN) is the most frequently reported pathology in patients with checkpoint inhibitor (CPI) induced acute kidney injury (AKI). Glucocorticoid (GC) therapy and discontinuation of CPI are the mainstay of treatment to prevent permanent renal dysfunction and dialysis. However, less than 50% of patients have complete kidney recovery and relapse of ATIN can occur. Infliximab is effective in treating other immune-related adverse events but its use for the treatment of CPI-ATIN is not well established. We report the first retrospective study examining the steroid-sparing potential of infliximab in achieving durable and complete renal recovery for patients with CPI-ATIN. Data were collected from medical records of patients diagnosed with CPI-AKI with a kidney biopsy or clinical diagnosis of ATIN that was managed with GC and infliximab. Infliximab-containing regimens were used to treat 10 patients with CPI-ATIN. Four patients relapsing after GC therapy achieved durable and complete renal recovery, four patients experienced partial renal recovery, and two patients showed no improvement in kidney function. This is the first study evaluating clinical outcomes using an infliximab-containing regimen for treatment of relapsed CPI-ATIN in patients or patients failing to achieve complete response after primary therapy. Our data suggest that infliximab may be a treatment option for achieving durable and complete renal recovery in this patient population and represents a potential steroid-sparing strategy in challenging cases of CPI-ATIN. Rigorous clinical studies are warranted to evaluate the risk-benefit analysis for infliximab usage in CPI-ATIN patients.


Assuntos
Nefrite Intersticial , Diálise Renal , Humanos , Infliximab/efeitos adversos , Rim , Nefrite Intersticial/induzido quimicamente , Estudos Retrospectivos
11.
J Immunother Cancer ; 9(10)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34625513

RESUMO

BACKGROUND: Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. METHODS: We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. RESULTS: ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. CONCLUSIONS: Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Idoso , Estudos de Coortes , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco
13.
J Immunother Cancer ; 8(2)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33020246

RESUMO

The same mechanisms that mediate antitumor immunity from checkpoint inhibitors (CPIs) can also lead to unintended targeting of normal tissues, characterized as immune-related adverse events (irAEs). Those with pre-existing autoimmune disease are believed to be particularly vulnerable for exacerbating underlying autoimmunity or inducing severe irAEs. We report the first case of CPI-associated reactivation of primary membranous nephropathy (MN) in a patient with pleural mesothelioma responding to immunotherapy. Due to its specificity in targeting B-lymphocytes, rituximab was used to treat primary MN with the expectation that this would not interfere with the benefits gained from T cell-mediated antitumor immunity. Rituximab was effective in treating CPI-associated reactivation of MN, and the patient was successfully rechallenged with nivolumab and maintained stable kidney function and sustained clinical antitumor effect. While exacerbation of pre-existing autoimmune diseases from CPIs is common, therapy for autoimmune reactivation can be rationally directed by an understanding of the immunosuppressive mechanism with goals of cancer treatment.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/métodos , Rituximab/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Glomerulonefrite Membranosa/induzido quimicamente , Glomerulonefrite Membranosa/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Rituximab/farmacologia
14.
J Immunother Cancer ; 8(2)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32718987

RESUMO

The percentage of patients with cancer eligible for checkpoint inhibitor (CPI) therapy has increased rapidly over the past few years and approaches 45%. As a result, more cases of CPI-related nephrotoxicity, including a rare subset with vasculitis, are being reported. To elucidate the clinical presentation of CPI-associated renal vasculitis and its possible mechanisms, treatment options and prognosis, we describe cases from a comprehensive cancer center and reviewed the literature for similar cases. We retrospectively reviewed the charts of all patients with cancer from 2014 to 2020 who were diagnosed with CPI-related nephrotoxicity and underwent a kidney biopsy. We identified five cases of renal vasculitis: three patients were diagnosed with seronegative antineutrophil cytoplasm antibody (ANCA)-associated vasculitis, one case with seropositive ANCA-associated vasculitis and one case was diagnosed with IgA vasculitis. Of these cases, four patients were receiving nivolumab, and one patient was receiving tremelimumab. All patients had microscopic hematuria, four out of five patients had negative ANCA serology, one patient had concurrent lung involvement and positive ANCA serology, and all had severe acute kidney injury with creatinine >4.50 mg/dL on diagnosis. All patients were treated by discontinuing CPI and initiating corticosteroids and rituximab. Three patients received plasmapheresis; two of these required renal replacement therapy including the patient with lung involvement. All patients after rituximab had a partial or complete renal response. Two patients died within 8 months of diagnosis due to malignancy progression. None of the patients had a relapse of vasculitis. We demonstrated that CPI can be associated with different types of renal vasculitis that are predominantly ANCA negative and manifest as severe acute kidney injury. Despite the lack of strong evidence, treatment similar to treatment of primary seropositive ANCA-associated vasculitis with corticosteroids and rituximab is well tolerated with favorable renal outcomes.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Ativação Linfocitária/imunologia , Rituximab/uso terapêutico , Adulto , Idoso , Antineoplásicos Imunológicos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Rituximab/farmacologia
15.
J Clin Invest ; 129(7): 2807-2823, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31063459

RESUMO

Phosphorylation of Dynamin-related protein1 (Drp1) represents an important regulatory mechanism for mitochondrial fission. Here we established the role of Drp1 Serine 600 (S600) phosphorylation on mitochondrial fission in vivo, and assessed the functional consequences of targeted elimination of the Drp1S600 phosphorylation site in progression of diabetic nephropathy (DN). We generated a knockin mouse in which S600 was mutated to alanine (Drp1S600A). We found that diabetic Drp1S600A mice exhibited improved biochemical and histological features of DN along with reduced mitochondrial fission and diminished mitochondrial ROS in vivo. Importantly, we observed that the effect of Drp1S600 phosphorylation on mitochondrial fission in the diabetic milieu was stimulus- but not cell type-dependent. Mechanistically, we showed that mitochondrial fission in high glucose conditions occurs through concomitant binding of phospho-Drp1S600 with mitochondrial fission factor (Mff) and actin-related protein 3 (Arp3), ultimately leading to accumulation of F-actin and Drp1 on the mitochondria. Taken together, these findings establish that a single phosphorylation site in Drp1 can regulate mitochondrial fission and progression of DN in vivo, and highlight the stimulus-specific consequences of Drp1S600 phosphorylation on mitochondrial dynamics.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Dinaminas/metabolismo , Mutação de Sentido Incorreto , Proteína 3 Relacionada a Actina/genética , Proteína 3 Relacionada a Actina/metabolismo , Substituição de Aminoácidos , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Dinaminas/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Dinâmica Mitocondrial , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Fosforilação/genética
16.
Cell Signal ; 46: 1-14, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29462661

RESUMO

Metastatic castration-resistant (CR) prostate cancer (PCa) is a lethal disease for which no effective treatment is currently available. p66Shc is an oxidase previously shown to promote androgen-independent cell growth through generation of reactive oxygen species (ROS) and is elevated in clinical PCa and multiple CR PCa cell lines. We hypothesize p66Shc also increases the migratory activity of PCa cells through ROS and investigate the associated mechanism. Using the transwell assay, our study reveals that the level of p66Shc protein correlates with cell migratory ability across several PCa cell lines. Furthermore, we show hydrogen peroxide treatment induces migration of PCa cells that express low levels of p66Shc in a dose-dependent manner, while antioxidants inhibit migration. Conversely, PCa cells that express high levels of endogenous p66Shc or by cDNA transfection possess increased cell migration which is mitigated upon p66Shc shRNA transfection or expression of oxidase-deficient dominant-negative p66Shc W134F mutant. Protein microarray and immunoblot analyses reveal multiple proteins, including ErbB-2, AKT, mTOR, ERK, FOXM1, PYK2 and Rac1, are activated in p66Shc-elevated cells. Their involvement in PCa migration was examined using respective small-molecule inhibitors. The role of Rac1 was further validated using cDNA transfection and, significantly, p66Shc is found to promote lamellipodia formation through Rac1 activation. In summary, the results of our current studies clearly indicate p66Shc also regulates PCa cell migration through ROS-mediated activation of migration-associated proteins, notably Rac1.


Assuntos
Neoplasias de Próstata Resistentes à Castração/patologia , Espécies Reativas de Oxigênio/metabolismo , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/fisiologia , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Movimento Celular , Humanos , Peróxido de Hidrogênio/farmacologia , Masculino , Pseudópodes , Transdução de Sinais , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/antagonistas & inibidores , Proteínas rac1 de Ligação ao GTP/fisiologia
17.
Nat Biotechnol ; 22(4): 411-7, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15024388

RESUMO

The hair follicle bulge possesses putative epithelial stem cells. Characterization of these cells has been hampered by the inability to target bulge cells genetically. Here, we use a Keratin1-15 (Krt1-15, also known as K15) promoter to target mouse bulge cells with an inducible Cre recombinase construct or with the gene encoding enhanced green fluorescent protein (EGFP), which allow for lineage analysis and for isolation of the cells. We show that bulge cells in adult mice generate all epithelial cell types within the intact follicle and hair during normal hair follicle cycling. After isolation, adult Krt1-15-EGFP-positive cells reconstituted all components of the cutaneous epithelium and had a higher proliferative potential than Krt1-15-EGFP-negative cells. Genetic profiling of hair follicle stem cells revealed several known and unknown receptors and signaling pathways important for maintaining the stem cell phenotype. Ultimately, these findings provide potential targets for the treatment of hair loss and other disorders of skin and hair.


Assuntos
Células Epiteliais/citologia , Técnicas Genéticas , Folículo Piloso/fisiologia , Células-Tronco/citologia , Células 3T3 , Animais , Divisão Celular , Linhagem Celular , Linhagem da Célula , Separação Celular , DNA Complementar/metabolismo , Fibroblastos/metabolismo , Citometria de Fluxo , Proteínas de Fluorescência Verde , Folículo Piloso/metabolismo , Queratinócitos/metabolismo , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas , RNA/metabolismo , RNA Mensageiro/metabolismo , Recombinases/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Gênica , Regulação para Cima
18.
PLoS One ; 12(9): e0184575, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28880939

RESUMO

ADP-ribosylation factor 6 (ARF6) is a small GTPase necessary for regulating cellular structure, motility, and vesicle trafficking. In several cellular systems, ARF6 was shown to regulate actin dynamics in coordination with Rac1, a Rho small GTPase. We examined the function of ARF6 in the kidney podocyte because Rac1 was implicated in kidney diseases involving this cell. We found that ARF6 expression was enriched in human podocytes and that it modulated podocyte cytoskeletal dynamics through a functional interaction with nephrin, an intercellular junction protein necessary for podocyte injury-induced signaling requiring activation by tyrosine phosphorylation of its cytoplasmic domain. ARF6 was necessary for nephrin activation-induced ruffling and focal adhesion turnover, possibly by altering Rac1 activity. In podocyte-specific Arf6 (ARF6_PodKO) knockout mice, ARF6 deficiency did not result in a spontaneous kidney developmental phenotype or proteinuria after aging. However, ARF6_PodKO mice exhibited distinct phenotypes in two in vivo glomerular injury models. In the protamine sulfate perfusion model, which induced acute podocyte effacement, ARF6_PodKO mice were protected from podocyte effacement. In the nephrotoxic serum nephritis model, which induced immune-complex mediated injury, ARF6_PodKO mice exhibited aggravated proteinuria. Together, these observations suggest that while ARF6 is necessary for nephrin tyrosine phosphorylation-induced cytoskeletal dynamics in cultured podocytes, ARF6 has pleotropic podocyte roles in vivo, where glomerular injury-specific mechanisms might activate distinct signaling pathways that dictate whether ARF6 activity is beneficial or deleterious for maintaining the integrity of the glomerular filtration barrier.


Assuntos
Fatores de Ribosilação do ADP/metabolismo , Nefrite/metabolismo , Fator 6 de Ribosilação do ADP , Fatores de Ribosilação do ADP/genética , Animais , Feminino , Humanos , Rim/metabolismo , Rim/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nefrite/genética , Podócitos/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Transdução de Sinais
19.
Oncogene ; 24(48): 7203-12, 2005 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-16170380

RESUMO

p66(Shc), an isoform of Shc adaptor proteins, is shown to mediate various signals, including cellular stress. However, little is known about its involvement in carcinogenesis. We previously showed that p66(Shc) protein level is upregulated by steroid hormones in human carcinoma cells and is higher in prostate cancer (PCa) specimens than adjacent noncancerous cells. In this study, we investigated the role of p66(Shc) protein in PCa cell proliferation. Among different PCa cell lines tested, p66(Shc) protein level showed positive correlation with cell proliferation, that is, rapid-growing cells expressed higher p66(Shc) protein than slow-growing cells. Exposure of slow-growing LNCaP C-33 cells to epidermal growth factor (EGF) and 5alpha-dihydrotestosterone (DHT) led to upregulation of proliferation and p66(Shc) protein level. Conversely, growth suppression of fast-growing cells by cellular form of prostatic acid phosphatase (cPAcP) expression, a negative growth regulator, down-regulated their p66(Shc) protein level. Additionally, increased expression of p66(Shc) protein by cDNA transfection in LNCaP C-33 cells resulted in increased cell proliferation. Cell cycle analyses showed higher percentage of p66(Shc)-overexpressing cells at S phase (24%) than control cells (17%), correlating with their growth rates. On the other hand, transient knock-down of p66(Shc) expression by RNAi in rapidly growing cells decreased their proliferation as evidenced by the reduced cell growth as well as S phase in p66(Shc)-knocked down cells. The p66(Shc) signaling in cell growth regulation is apparently mediated by extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK). Thus, our results indicate a novel role for p66(Shc) in prostate carcinogenesis, in part, promoting cell proliferation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Fosfatase Ácida , Proteínas Adaptadoras de Transdução de Sinal/genética , Linhagem Celular Tumoral , Células Clonais , Di-Hidrotestosterona/farmacologia , Fator de Crescimento Epidérmico/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Masculino , Fosforilação , Neoplasias da Próstata/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Tirosina Fosfatases/farmacologia , Interferência de RNA , Fase S , Proteínas Adaptadoras da Sinalização Shc , Transdução de Sinais , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src , Regulação para Cima/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA