RESUMO
Signal-transducing adaptor protein (STAP)-1 is an adaptor protein that is widely expressed in T cells. In this article, we show that STAP-1 upregulates TCR-mediated T cell activation and T cell-mediated airway inflammation. Using STAP-1 knockout mice and STAP-1-overexpressing Jurkat cells, we found that STAP-1 enhanced TCR signaling, resulting in increased calcium mobilization, NFAT activity, and IL-2 production. Upon TCR engagement, STAP-1 binding to ITK promoted formation of ITK-LCK and ITK-phospholipase Cγ1 complexes to induce downstream signaling. Consistent with the results, STAP-1 deficiency reduced the severity of symptoms in experimental autoimmune encephalomyelitis. Single-cell RNA-sequencing analysis revealed that STAP-1 is essential for accumulation of T cells and Ifng and Il17 expression in spinal cords after experimental autoimmune encephalomyelitis induction. Th1 and Th17 development was also attenuated in STAP-1 knockout naive T cells. Taken together, STAP-1 enhances TCR signaling and plays a role in T cell-mediated immune disorders.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Encefalomielite Autoimune Experimental , Inflamação , Animais , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/genética , Inflamação/metabolismo , Inflamação/patologia , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T , Transdução de SinaisRESUMO
Signal-transducing adaptor protein-2 (STAP-2) is an adaptor protein that contains pleckstrin and Src homology 2-like domains, as well as a proline-rich region in its C-terminal region. Our previous study demonstrated that STAP-2 positively regulates TCR signaling by associating with TCR-proximal CD3ζ ITAMs and the lymphocyte-specific protein tyrosine kinase. In this study, we identify the STAP-2 interacting regions of CD3ζ ITAMs and show that the STAP-2-derived synthetic peptide (iSP2) directly interacts with the ITAM sequence and blocks the interactions between STAP-2 and CD3ζ ITAMs. Cell-penetrating iSP2 was delivered into human and murine T cells. iSP2 suppressed cell proliferation and TCR-induced IL-2 production. Importantly, iSP2 treatment suppressed TCR-mediated activation of naive CD4+ T cells and decreased immune responses in CD4+ T cell-mediated experimental autoimmune encephalomyelitis. It is likely that iSP2 is a novel immunomodulatory tool that modulates STAP-2-mediated activation of TCR signaling and represses the progression of autoimmune diseases.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Transdução de Sinais , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Imunidade , Receptores de Antígenos de Linfócitos T/metabolismo , Fragmentos de Peptídeos/farmacologiaRESUMO
Signal-transducing adaptor family member-2 (STAP-2) is an adaptor protein that regulates various intracellular signals. We previously demonstrated that STAP-2 binds to epidermal growth factor receptor (EGFR) and facilitates its stability and activation of EGFR signaling in prostate cancer cells. Inhibition of this interaction may be a promising direction for cancer treatment. Here, we found that 2D5 peptide, a STAP-2-derived peptide, blocked STAP-2-EGFR interactions and suppressed EGFR-mediated proliferation in several cancer cell lines. 2D5 peptide inhibited tumor growth of human prostate cancer cell line DU145 and human lung cancer cell line A549 in murine xenograft models. Additionally, we determined that EGFR signaling and its stability were decreased by 2D5 peptide treatment during EGF stimulation. In conclusion, our study shows that 2D5 peptide is a novel anticancer peptide that inhibits STAP-2-mediated activation of EGFR signaling and suppresses prostate and lung cancer progression.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Neoplasias Pulmonares , Peptídeos , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias da Próstata/metabolismo , Transdução de Sinais , Células A549 , Linhagem Celular Tumoral , Peptídeos/farmacologiaRESUMO
Melanoma, originating from melanocytes, is a highly aggressive tumor. Tyrosinase is involved in melanin production in melanocytes, and its overexpression is noted in malignant melanomas. However, the role of tyrosinase in melanomas remains unclear. Therefore, this study aimed to evaluate the potential functions of tyrosinase in the human melanoma cell line A375. The expression level of tyrosinase in A375 cells was undetectable. However, markedly increased expression level was observed in the mouse melanoma cell line B16F10 and the human melanoma cell line WM266-4. Subsequently, we investigated the effect of ectopic tyrosinase expression on A375 cell motility using wound-healing assay. The overexpression of tyrosinase resulted in enhanced cell migration in both stable and transient tyrosinase expression cells. The levels of filamentous actin were decreased in tyrosinase-expressing A375 cells, suggesting that tyrosinase regulates cell motility by modulating actin polymerization. Histidine residues in tyrosinase are important for its enzymatic activity for synthesizing melanin. Substitution of these histidine residues to alanine residues mitigated the promotion of tyrosinase-induced A375 cell metastasis. Furthermore, melanin treatment enhanced A375 cell metastasis and phosphorylation of Cofilin. Thus, our findings suggest that tyrosinase increases the migration of A375 cells by regulating actin polymerization through its enzymatic activity.
Assuntos
Melaninas , Melanoma Experimental , Animais , Camundongos , Humanos , Melaninas/metabolismo , Monofenol Mono-Oxigenase/genética , Monofenol Mono-Oxigenase/metabolismo , Oxigenases de Função Mista/metabolismo , Actinas/metabolismo , Histidina/metabolismo , Melanoma Experimental/patologia , Linhagem Celular Tumoral , Melanócitos/metabolismoRESUMO
Damage-associated molecular patterns (DAMPs) contribute to antitumor immunity during cancer chemotherapy. We previously demonstrated that topotecan (TPT), a topoisomerase I inhibitor, induces DAMP secretion from cancer cells, which activates STING-mediated antitumor immune responses. However, how TPT induces DAMP secretion in cancer cells is yet to be elucidated. Here, we identified RPL15, a 60S ribosomal protein, as a novel TPT target and showed that TPT inhibited preribosomal subunit formation via its binding to RPL15, resulting in the induction of DAMP-mediated antitumor immune activation independent of TOP1. TPT inhibits RPL15-RPL4 interactions and decreases RPL4 stability, which is recovered by CDK12 activity. RPL15 knockdown induced DAMP secretion and increased the CTL population but decreased the regulatory T cell population in a B16-F10 murine melanoma model, which sensitized B16-F10 tumors against PD-1 blockade. Our study identified a novel TPT target protein and showed that ribosomal stress is a trigger of DAMP secretion, which contributes to antitumor immunotherapy.
Assuntos
Neoplasias , Topotecan , Animais , Camundongos , Neoplasias/tratamento farmacológico , Proteínas Ribossômicas , Inibidores da Topoisomerase I/farmacologia , Topotecan/farmacologia , Topotecan/uso terapêuticoRESUMO
TCR ligation with an Ag presented on MHC molecules promotes T cell activation, leading to the selection, differentiation, and proliferation of T cells and cytokine production. These immunological events are optimally arranged to provide appropriate responses against a variety of pathogens. We here propose signal-transducing adaptor protein-2 (STAP-2) as a new positive regulator of TCR signaling. STAP-2-deficient T cells showed reduced, whereas STAP-2-overexpressing T cells showed enhanced, TCR-mediated signaling and downstream IL-2 production. For the mechanisms, STAP-2 associated with TCR-proximal CD3ζ immunoreceptor tyrosine activation motifs and phosphorylated LCK, resulting in enhancement of their binding after TCR stimulation. In parallel, STAP-2 expression is required for full activation of downstream TCR signaling. Importantly, STAP-2-deficient mice exhibited slight phenotypes of CD4+ T-cell-mediated inflammatory diseases, such as experimental autoimmune encephalomyelitis, whereas STAP-2-overexpressing transgenic mice showed severe phenotypes of these diseases. Together, STAP-2 is an adaptor protein to enhance TCR signaling; therefore, manipulating STAP-2 will have an ability to improve the treatment of patients with autoimmune diseases as well as the chimeric Ag receptor T cell therapy.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Transdução de Sinais , Animais , Ativação Linfocitária , Camundongos , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos TRESUMO
Jak3, a member of the Janus kinase family, is essential for the cytokine receptor common gamma chain (γc)-mediated signaling. During activation of Jak3, tyrosine residues are phosphorylated and potentially regulate its kinase activity. We identified a novel tyrosine phosphorylation site within mouse Jak3, Y820, which is conserved in human Jak3, Y824. IL-2-induced tyrosine phosphorylation of Jak3 Y824 in human T cell line HuT78 cells was detected by using a phosphospecific, pY824, antibody. Mutation of mouse Jak3 Y820 to alanine (Y820A) showed increased autophosphorylation of Jak3 and enhanced signal transducer and activator of transcription 5 (STAT5) tyrosine phosphorylation and transcriptional activation. Stably expressed Jak3 Y820A in F7 cells, an IL-2 responsive mouse pro-B cell line Ba/F3, exhibited enhanced IL-2-dependent cell growth. Mechanistic studies demonstrated that interaction between Jak3 and STAT5 increased in Jak3 Y820A compared to wild-type Jak3. These data suggest that Jak3 Y820 plays a role in negative regulation of Jak3-mediated STAT5 signaling cascade upon IL-2-stimulation. We speculate that this occurs through an interaction promoted by the tyrosine phosphorylated Y820 or a conformational change by Y820 mutation with either the STAT directly or with the recruitment of molecules such as phosphatases via a SH2 interaction. Additional studies will focus on these interactions as Jak3 plays a crucial role in disease and health.
Assuntos
Fator de Transcrição STAT5 , Tirosina , Animais , Interleucina-2/metabolismo , Interleucina-2/farmacologia , Janus Quinase 3 , Camundongos , Proteínas do Leite/metabolismo , Fosforilação , Fator de Transcrição STAT5/metabolismo , Transdução de SinaisRESUMO
The interleukin 6 (IL-6) family of cytokines is defined by the usage of gp130, a common ß-receptor signaling subunit, which promotes a variety of signals. They induce many biological functions on many cell types, including immune and inflammatory cells. They also exhibit hormone-like features, which are involved in homeostatic processes. Signal transducer and activator of transcription 3 (STAT3) is a significant signaling molecule fundamental in regulating IL-6/gp130 and is highly implicated in pathological conditions; therefore, STAT3 activation is tightly regulated through various mechanisms and at multiple levels. There is a large amount of information about STAT3-interacting proteins, which positively or negatively regulate STAT3 activity. This review is focused on IL-6-mediated signal transduction and the introduction of novel STAT3-binding partners. The review will help develop new strategies for clinically controlling the functions of IL-6/STAT3.
Assuntos
Interleucina-6 , Fator de Transcrição STAT3 , Receptor gp130 de Citocina , Citocinas , Transdução de SinaisRESUMO
Interleukin-17A (IL-17A) is a cytokine that affects the functions of non-immune cells, including keratinocytes, and thereby amplifies immune responses. An IκB family protein IκB-ζ, encoded by the NFKBIZ gene, mediates IL-17A-induced inflammatory cellular responses. Previously we reported that a transcription factor STAT3 mediates the transcriptional induction of NFKBIZ through its binding to the specific binding site existing in the NFKBIZ promoter. However, it remains unclear how other transcription factors regulate NFKBIZ transcription. Here, we investigated the NFKBIZ promoter regulation by transcription factors C/EBPß and STAT1 and revealed opposing roles of C/EBPß and STAT1 in NFKBIZ transcription. We found that siRNA-mediated knockdown of C/EBPß attenuates IL-17A-induced upregulation of NFKBIZ in the HaCaT cell line. A putative C/EBP-binding site is located adjacent to the STAT-binding site in the NFKBIZ promoter, the deletion of which abolished C/EBPß-driven promoter activation in transient NFKBIZ promoter-luciferase assay. Deleting the STAT-binding site also led to a reduction in C/EBPß-driven promoter activation, suggesting a cooperative action between C/EBP- and STAT-binding sites. Furthermore, Co-overexpression of STAT1 suppressed both C/EBPß- and STAT3-driven NFKBIZ promoter activation independently of its tyrosine 701 phosphorylation. siRNA-mediated STAT1 knockdown augmented IκB-ζ induction in IL-17A-treated HaCaT cells, with enhanced expression of an IκB-ζ target gene DEFB4A. Together, these results indicate that both C/EBPß and STAT3 are transcription factors that coordinately induce NFKBIZ promoter activation, indicating that STAT1 has an inhibitory role. Thus, these could be a fine-tuning mechanism of IL-17A-IκB-ζ-mediated cellular responses.
Assuntos
Proteína beta Intensificadora de Ligação a CCAAT , Interleucina-17 , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Regulação da Expressão Gênica , Interleucina-17/metabolismo , Regiões Promotoras Genéticas , RNA Interferente Pequeno/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismoRESUMO
CD47, a 50 kDa transmembrane protein, facilitates integrin-mediated cell adhesion and inhibits cell engulfment by phagocytes. Since CD47 blocking promotes engulfment of cancer cells by macrophages, it is important to clarify the mechanism of CD47 signaling in order to develop treatments for diseases involving CD47-overexpressing cancer cells, including breast cancer and lymphoma. Here, we show that CD47 plays an essential role in T-cell lymphoma metastasis by up-regulating basal RhoA activity independent of its anti-phagocytic function. CD47 interacts with AKAP13, a RhoA-specific guanine nucleotide exchange factor (GEF), and facilitates AKAP13-mediated RhoA activation. Our study shows that CD47 has a novel function on the AKAP13-RhoA axis and suggests that CD47-AKAP13 interaction would be a novel target for T-cell lymphoma treatment.
Assuntos
Proteínas de Ancoragem à Quinase A/metabolismo , Antígeno CD47/metabolismo , Linfoma de Células T/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Metástase Neoplásica/patologia , Proteínas Proto-Oncogênicas/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Linfoma de Células T/patologia , Macrófagos/metabolismo , Fagocitose , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologiaRESUMO
The purpose of this study was to investigate the psychological impact of various positionings in subjects with cerebral palsy (CP). The participants were 17 individuals with severe motor and intellectual disability due to CP. They began in a sitting position in their wheelchair, and were placed consecutively in prone or supine positions, with no intervals between placements. Physiological observations were made in each position, and included salivary α-amylase activity, pulse, percutaneous oxygen saturation, respiratory rate, learance or not of airway secretions, and occurrence or not of adverse events. Salivary α-amylase activity values were higher in the prone position than in the baseline and supine positions (p<0.05). Clearance of airway secretions was significantly more prevalent in the prone position than in the baseline and supine positions (p <0.05). The participants' pulse was significantly lower in the supine and prone positions than in the baseline position (p<0.05). Greater prevalence of airway secretion clearance and significantly higher stress levels as indicated by saliva amylase were observed in the prone position than in the other two positions. Therefore, when such patients are placed in a prone position, close attention to airway management and the potential for psychological stress may be necessary.
Assuntos
Paralisia Cerebral , alfa-Amilases Salivares , Humanos , Decúbito Ventral/fisiologia , Posicionamento do Paciente/efeitos adversos , Estresse Psicológico/etiologiaRESUMO
OBJECTIVE: We validated the Japanese version of the ureteral stent symptom questionnaire in patients with an indwelling ureteric stent. METHODS: The English version of the ureteral stent symptom questionnaire was translated into Japanese using a multistep process by three urologists and two independent translators. A total of 70 patients with indwelling ureteral stents completed the Japanese ureteral stent symptom questionnaire, as well as validated instruments, namely, the International Prostate Symptom Score or Overactive Bladder Symptom Score and the EuroQoL 5-dimension questionnaires. Patients completed questionnaires at 2 weeks after stent insertion and 4 weeks after stent removal. The second group included 87 healthy individuals who agreed to complete the questionnaires. The reliability of the Japanese version was evaluated for internal consistency using Cronbach's α test. Psychometric properties of the questionnaire were analyzed, and included convergent validity, sensitivity to change and discriminant validity. RESULTS: A total of 70 cases and 87 controls were suitable for the analysis. A comparison of patients with ureteric stents and healthy individuals was carried out, and the convergent validity determined by the correlation between other instruments and the corresponding ureteral stent symptoms questionnaire domains was satisfactory (P < 0.05). Internal consistencies (Cronbach's α coefficients 0.73-0.80) were satisfactory, except for the sexual matters domain. Test-retest reliability was good, except for the sexual matters domain (Spearman's coefficient 0.71-0.93). CONCLUSIONS: The Japanese version of the ureteral stent symptom questionnaire proved to be a reliable and robust instrument for the evaluation of ureteral stent-associated morbidity for both men and women.
Assuntos
Qualidade de Vida , Stents , Feminino , Humanos , Japão , Linguística , Masculino , Psicometria , Reprodutibilidade dos Testes , Stents/efeitos adversos , Inquéritos e QuestionáriosRESUMO
Primary aldosteronism is most often caused by aldosterone-producing adenoma (APA) and bi-lateral adrenal hyperplasia. Most APAs are caused by somatic mutations of various ion channels and pumps, the most common being the inward-rectifying potassium channel KCNJ5. Germ line mutations of KCNJ5 cause familial hyperaldosteronism type 3 (FH3), which is associated with severe hyperaldosteronism and hypertension. We present an unusual case of FH3 in a young woman, first diagnosed with primary aldosteronism at the age of 6 years, with bilateral adrenal hyperplasia, who underwent unilateral adrenalectomy (left adrenal) to alleviate hyperaldosteronism. However, her hyperaldosteronism persisted. At the age of 26 years, tomography of the remaining adrenal revealed two different adrenal tumors, one of which grew substantially in 4 months; therefore, the adrenal gland was removed. A comprehensive histological, immunohistochemical, and molecular evaluation of various sections of the adrenal gland and in situ visualization of aldosterone, using matrix-assisted laser desorption/ionization imaging mass spectrometry, was performed. Aldosterone synthase (CYP11B2) immunoreactivity was observed in the tumors and adrenal gland. The larger tumor also harbored a somatic ß-catenin activating mutation. Aldosterone visualized in situ was only found in the subcapsular regions of the adrenal and not in the tumors. Collectively, this case of FH3 presented unusual tumor development and histological/molecular findings.
RESUMO
Chronic myeloid leukemia (CML) is a clonal disease characterized by the presence of the Philadelphia chromosome and its oncogenic product, BCR-ABL, which activates multiple pathways involved in cell survival, growth promotion, and disease progression. We recently reported that signal-transducing adaptor protein 1 (STAP-1) is upregulated in CML stem cells (LSCs) and functions to reduce the apoptosis of CML LSCs by upregulating the STAT5-downstream anti-apoptotic genes. In this study, we demonstrate the detailed molecular interactions among BCR-ABL, STAP-1, and signal transducer and activator of transcription 5 (STAT5). Studies with deletion mutants have revealed that STAP-1 interacts with BCR-ABL and STAT5a through its SH2 and PH domains, respectively, suggesting the possible role of STAP-1 as a scaffold protein. Furthermore, the binding of STAP-1 to BCR-ABL stabilizes the BCR-ABL protein in CML cells. Since STAP-1 is highly expressed in CML cells, we also analyzed the STAP-1 promoter activity using a luciferase reporter construct and found that NFATc1 is involved in activating the STAP-1 promoter and inducing STAP-1 mRNA expression. Our results demonstrate that STAP-1 contributes to the BCR-ABL/STAT5 and BCR-ABL/Ca2+/NFAT signals to induce proliferation and STAP-1 mRNA expression in CML cells, respectively.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proliferação de Células , Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Linhagem Celular Tumoral , Sobrevivência Celular , Proteínas de Fusão bcr-abl/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores de Transcrição NFATC/metabolismo , Ligação Proteica , Domínios Proteicos , Estabilidade Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
Signal-transducing adaptor protein (STAP)-2 is one of the STAP family adaptor proteins and ubiquitously expressed in a variety types of cells. Although STAP-2 is required for modification of FcεRI signal transduction in mast cells, other involvement of STAP-2 in mast cell functions is unknown, yet. In the present study, we mainly investigated functional roles of STAP-2 in IL-33-induced mast cell activation. In STAP-2-deficient, but not STAP-1-deficient, mast cells, IL-33-induced IL-6 and TNF-α production was significantly decreased compared with that of wild-type mast cells. In addition, STAP-2-deficiency greatly reduced TLR4-mediated mast cell activation and cytokine production. For the mechanisms, STAP-2 directly binds to IKKα after IL-33 stimulation, leading to elevated NF-κB activity. In conclusion, STAP-2, but not STAP-1, participates in IL-33-induced mast cells activation.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Interleucina-33/metabolismo , Mastócitos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Animais , Células Cultivadas , Citocinas/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Graft-versus-host disease (GVHD) is the most frequent complication after allogeneic hematopoietic stem cell transplantation (HSCT), and is one of the major causes of non-relapse mortality. Transferred mature lymphocytes are thought to be responsible for GVHD based on the findings that mice transplanted with lymphocyte-depleted bone marrow (BM) cells from MHC-mismatched donors do not develop GVHD. However, we found that overexpression of signal-transducing adaptor protein (STAP)-2 in lymphoid cells could induce GVHD after lymphocyte-depleted BM transplantation. To examine the function of STAP-2, which has been shown to play an important role in development and function of lymphocytes, in GVHD, we transplanted BM cells from STAP-2 deficient, or Lck promoter/IgH enhancer-driven STAP-2 transgenic (Tg) mice into MHC-mismatched recipients. Unexpectedly, mice transplanted with lymphocyte-depleted BM cells from STAP-2 Tg mice developed severe acute GVHD with extensive colitis and atrophy of thymus, while no obvious GVHD developed in mice transplanted with the wild type or STAP-2 deficient graft. Furthermore, mice transplanted with lymphocyte-depleted BM cells from the syngeneic STAP-2 Tg mice developed modest GVHD with colitis and atrophy of thymus. These results suggest that STAP-2 overexpression may enhance survival of allo-, and even auto-, reactive lymphocytes derived from engrafted hematopoietic progenitor cells in lethally irradiated mice, and that clarification of the mechanism may help understanding induction of immune tolerance after HSCT.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células da Medula Óssea/imunologia , Transplante de Medula Óssea , Doença Enxerto-Hospedeiro/imunologia , Depleção Linfocítica , Doença Aguda , Animais , Contagem de Linfócitos , Complexo Principal de Histocompatibilidade , Camundongos Transgênicos , Linfócitos T Reguladores/imunologia , Transplante HomólogoRESUMO
BACKGROUND: The loss of PBRM1 expression (as identified by immunohistochemistry) is associated with a high risk of postoperative recurrence for patients with clear cell renal cell carcinoma (ccRCC). The authors developed a scoring system to predict recurrence based on clinicopathologic factors incorporating PBRM1 expression. METHODS: This study retrospectively reviewed 479 ccRCC patients who underwent radical surgery between 2006 and 2017. The study extracted a subset of 389 non-metastatic ccRCC patients for whom relevant clinicopathologic factors were available. The primary end point was recurrence-free survival (RFS). The Kaplan-Meier method and the Cox proportional hazards model were used for statistical analysis. Leibovich score, SSIGN score, and University of California, Los Angeles (UCLA) Integrated Staging System were included as conventional prediction models. RESULTS: Of the 389 patients, 53 (13.6%) experienced recurrence during a median period of 61 months. Multivariable analyses showed that that the independent factors for RFS were ≥ pT3 (hazard ratio [HR] 3.64; P < 0.001), sarcomatoid or rhabdoid component (HR 3.29; P = 0.005), PBRM1 negativity (HR 3.39; P = 0.001), and necrosis (HR 3.60; P < 0.001). A scoring system calculated with these factors, named the SSPN (stage, sarcomatoid, PBRM1 expression, and necrosis) score, showed significant differences in RFS among the following four groups; low-risk group (0 factors), intermediate-risk group (1 factor), high-risk group (2 to 3 factors), and very high-risk group (4 factors) (P < 0.001). The authors' model also showed a greater predictive accuracy for 5-year RFS than the conventional models (0.841 vs 0.747-0.792). CONCLUSIONS: The SSPN score, which integrates clinicopathologic findings and PBRM1 expression, can accurately predict postoperative recurrence for patients with non-metastatic ccRCC after radical surgery.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/cirurgia , Proteínas de Ligação a DNA , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/cirurgia , Recidiva Local de Neoplasia/cirurgia , Nefrectomia , Prognóstico , Estudos Retrospectivos , Fatores de TranscriçãoRESUMO
Signal-transducing adaptor protein-2 (STAP-2) was discovered as a C-FMS/M-CSFR interacting protein and subsequently found to function as an adaptor of signaling or transcription factors. These include STAT5, MyD88 and IκB kinase in macrophages, mast cells, and T cells. There is additional information about roles for STAP-2 in several types of malignant diseases including chronic myeloid leukemia, however, none have been reported concerning B lineage lymphocytes. We have now exploited gene targeted and transgenic mice to address this lack of knowledge, and demonstrated that STAP-2 is not required under normal, steady-state conditions. However, recovery of B cells following transplantation was augmented in the absence of STAP-2. This appeared to be restricted to cells of B cell lineage with myeloid rebound noted as unremarkable. Furthermore, all hematological parameters were observed to be normal once recovery from transplantation was complete. Furthermore, overexpression of STAP-2, specifically in lymphoid cells, resulted in reduced numbers of late-stage B cell progenitors within the bone marrow. While numbers of mature peripheral B and T cells were unaffected, recovery from sub-lethal irradiation or transplantation was dramatically reduced. Lipopolysaccharide (LPS) normally suppresses B precursor expansion in response to interleukin 7, however, STAP-2 deficiency made these cells more resistant. Preliminary RNA-Seq analyses indicated multiple signaling pathways in B progenitors as STAP-2-dependent. These findings suggest that STAP-2 modulates formation of B lymphocytes in demand conditions. Further study of this adapter protein could reveal ways to speed recovery of humoral immunity following chemotherapy or transplantation.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Transplante de Células-Tronco Hematopoéticas , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linfócitos B/metabolismo , Macrófagos/metabolismo , Camundongos , Transdução de SinaisRESUMO
The signal-transducing adaptor protein (STAP) family, including STAP-1 and STAP-2, contributes to a variety of intracellular signaling pathways. The proteins in this family contain typical structures for adaptor proteins, such as Pleckstrin homology in the N-terminal regions and SRC homology 2 domains in the central regions. STAP proteins bind to inhibitor of kappaB kinase complex, breast tumor kinase, signal transducer and activator of transcription 3 (STAT3), and STAT5, during tumorigenesis and inflammatory/immune responses. STAP proteins positively or negatively regulate critical steps in intracellular signaling pathways through individually unique mechanisms. This article reviews the roles of the novel STAP family and the possible therapeutic applications of targeting STAP proteins in cancer.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinogênese/metabolismo , Neoplasias/metabolismo , Animais , Proteínas Sanguíneas/metabolismo , Humanos , Proteínas de Neoplasias/metabolismo , Fosfoproteínas/metabolismo , Proteínas Tirosina Quinases/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Tirosina/metabolismoRESUMO
Signal-transducing adaptor protein (STAP)-2 is an adaptor molecule involved in regulation of several intracellular signaling events in immune cells. STAP-2 contains a pleckstrin homology domain at the N-terminus, an src homology domain in the central portion and a proline-rich region at the C-terminus. STAP-2 also has a YXXQ motif, which is a potential signal transducer and activator of transcription (STAT)3-binding site. STAP-2 influences the STAT3 and STAT5 activity, integrin-mediated T cell adhesion, chemokine-induced T cell migration, Fas-mediated T cell apoptosis, Toll-like receptor-mediated macrophage functions, macrophage colony-stimulating factor-induced macrophage activation, and the high-affinity immunoglobulin E receptor-mediated mast cell activation. This article reviews the current understanding of roles of the STAP-2 during immune and/or inflammatory responses, and discusses possible therapeutic applications of targeting STAP-2 proteins in immune-related disorders.