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1.
Cureus ; 16(5): e60178, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38868263

RESUMO

Recent reports have focused on the usefulness of conversion surgery, in which chemotherapy is given to patients with unresectable advanced gastric cancer (GC), and radical surgery is subsequently performed if resection becomes possible; however, no consensus has been reached regarding the usefulness of this strategy. We report on a 74-year-old man who was diagnosed with esophagogastric junction cancer (T3N3M1 (LYM): stage IV). Chemotherapy was chosen and seven courses of S1 + cisplatin (SP) + trastuzumab (HCN) and two courses of S1 + HCN were administered. Approximately 10 months after the start of chemotherapy, the tumor had almost disappeared and we therefore decided to perform conversion surgery. Pathologic examination of the specimen and dissected lymph nodes showed no cancer. Postoperatively, the patient underwent chemotherapy until the second postoperative year, and no metastasis or recurrence was observed for nine years after surgery. Conversion surgery after chemotherapy resulted in recurrence-free survival in this case; however, further studies are needed to elucidate the effect of surgery after chemotherapy for patients with stage IV GC, as chemotherapy continues to evolve.

2.
World J Clin Cases ; 12(14): 2420-2425, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38765754

RESUMO

BACKGROUND: A Bochdalek hernia (BH) is a congenital diaphragmatic hernia that often develops in the neonatal period. BH typically occurs on the left side of the diaphragm. A right-sided BH in an adult is rare. CASE SUMMARY: A 45-year-old man was referred to our hospital because of an abnormal shadow seen on chest radiography during a medical check-up. A chest radiograph showed elevation of the right hemidiaphragm. Computed tomography showed prolapse of multiple intraabdominal organs into the right thoracic cavity, corresponding to a right-sided BH. The herniated contents included the stomach, transverse colon, and left lobe of the liver. The left lobe of the liver was enlarged, particularly the medial segment. Laparoscopic surgery was performed. However, the left lobe of the liver was completely trapped in the thoracic cavity. Therefore, thoracoscopic manipulation had to be performed to return the liver to the abdominal cavity. The hernia was repaired with interrupted nonabsorbable sutures and reinforced with mesh. CONCLUSION: Combined laparoscopic and thoracoscopic surgery was successfully performed for right-sided BH with massive liver prolapse and abnormal liver morphology.

3.
Updates Surg ; 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578408

RESUMO

Laparoscopic surgery has been used to treat gastric submucosal tumors (SMTs). Laparoscopic and endoscopic cooperative surgery (LECS) has been used when subtotal resection has been difficult, which enabled resection of these tumors. In this study, we reviewed the medical records of patients with gastric SMTs who underwent laparoscopic surgery in our hospital with the aim of reporting the surgical indications, procedures (especially for LECS), and outcomes of surgery. This study involved 55 patients who underwent laparoscopic surgery between April 2014 and March 2021. We classified the patients into two groups: laparoscopy-assisted surgery group (non-LECS group, n = 30) and LECS group (n = 25). LECS was performed in the upper stomach, in the greater curvature of the lower stomach, and in both intraluminal and intramural locations in the middle stomach. Non-LECS was selected for extraluminal and intramural tumors in the greater curvature of the upper stomach. There were no severe complications associated with the operation. There was one postoperative complication in the LECS group. The length of postoperative hospital stay did not significantly differ between the LECS and non-LECS groups. We reported the surgical procedures for gastric SMTs in our hospital. It is essential to make full use of the multiple techniques reported in this article and examine the location of the tumor to avoid excess or insufficient resection. Our review of the present case series allowed us to select the appropriate surgical approach for gastric SMTs based on the lesion location and type of development.

4.
J Laparoendosc Adv Surg Tech A ; 34(4): 354-358, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38359395

RESUMO

Background: Esophageal submucosal tumors (SMTs) are rare, occurring in less than 1% of esophageal neoplasms. For surgical treatment of esophageal SMTs, enucleation is usually the procedure of choice for benign tumors. This study aimed at evaluating the surgical technique and outcomes of thoracoscopic enucleation with esophagoscopy for esophageal SMTs. Methods: Patients with esophageal SMTs who underwent thoracoscopic enucleation between 2015 and 2022 were retrospectively investigated. Surgery was performed with the patient in the prone position. First, an esophagoscope was inserted, and a sodium hyaluronate solution with indigo carmine dye was injected into the submucosal layer just below the tumor. Next, under thoracoscopy, the tumor was exposed through a thoracoscopic incision and dissection of the muscularis propria and adventitia was performed at the tumor site. The colored layer resulting from the previously injected dye was identified, and tumor enucleation was performed under guidance of the dye so as not to damage the mucosa or pseudocapsule. Results: In total, 5 surgeries were performed. The mean operative time was 122.6 minutes (range 84-168 minutes), mean blood loss was 21.1 mL (range 0-80 mL), and mean postoperative hospital stay was 8 days (range 7-10 days). There were no postoperative complications. Pathological diagnosis revealed 2 cases of gastrointestinal stromal tumors, 2 cases of schwannoma, and 1 case of leiomyoma. Conclusions: We believe that this technique is a useful and safe method of performing thoracoscopic enucleation of esophageal SMTs because the injected dye provides an indicator of the resection line during enucleation.


Assuntos
Neoplasias Esofágicas , Esofagoscopia , Humanos , Esofagoscopia/métodos , Decúbito Ventral , Estudos Retrospectivos , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/patologia , Toracoscopia/métodos , Resultado do Tratamento
5.
Int J Surg Case Rep ; 114: 109183, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38154231

RESUMO

INTRODUCTION: Timely diagnosis and treatment of intra-abdominal arterial aneurysms before rupture are highly recommended. We successfully prevented rupture through arterial aneurysm excision, highlighting the importance of the lack of reports on resection before rupture. CASE PRESENTATION: A 60-year-old male with previous history of ureteral stones presented complaining primarily of left-sided abdominal pain. Computed tomography (CT) revealed a left ureteral stone and incidentally identified a submucosal gastric tumor and right gastric artery aneurysm, leading to referral to our department. Blood tests showed no abnormalities. CT revealed a 23-mm submucosal tumor protruding outward from the middle gastric body wall. A 13-mm aneurysm was observed in the right gastric artery, and no other aneurysms were detected, including intracranially. Upper gastrointestinal endoscopy revealed a smooth elevation covered by normal mucosa in the middle gastric body. Endoscopic ultrasound-fine needle aspiration resulted in a diagnosis of gastrointestinal stromal tumor (GIST) and surgery. We performed simultaneous surgery involving laparoscopic local resection of the gastric GIST and identification and excision of the right gastric artery aneurysm due to its enlargement (7 mm on CT conducted six years ago). The patient's postoperative course was uneventful, and he was discharged on postoperative day 6. Pathological examination confirmed a diagnosis of segmental arterial mediolysis. DISCUSSION: Intra-abdominal arterial aneurysms affect approximately 1 % of the population. Splenic artery aneurysms are the most common at 58.7 %, whereas the gastric artery and gastroepiploic artery account for only 4.7 %. CONCLUSION: Right gastric artery aneurysms are exceedingly rare, with no reported cases of successful resection before rupture.

6.
J Surg Case Rep ; 2023(8): rjad462, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37593192

RESUMO

The right top pulmonary vein (RTPV), a rare pulmonary vein (PV) variant draining the right upper lobe, arises independently from the right superior PV, travels posterior to the right bronchial tree and drains directly into the left atrium (LA) or another PV. We report an RTPV discovered on preoperative computed tomography (CT) scanning in a 60-y-old man who subsequently underwent prone thoracoscopic esophagectomy and subcarinal lymph node dissection. The preoperative CT scan showed an anomalous vessel 7.8 mm in diameter arising from the right upper lobe, running posterior to the right main bronchus (RMB), and draining directly into the LA. To our best knowledge, this is the largest reported RTPV (7.8 mm in diameter) and is an extremely rare variant, passing posterior to the RMB and draining into the LA.

7.
Gan To Kagaku Ryoho ; 48(13): 1898-1900, 2021 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-35045440

RESUMO

The case was a man in his 60s. With a complaint of loss of appetite, a peripheral type 3 lesion was found from the lower body of the stomach to the vestibule, and a biopsy revealed poorly differentiated adenocarcinoma. CT examination revealed that the tumor had invaded the left lobe of the liver and the transverse colon, and that the para-aortic lymph nodes were swollen and multiple nodules of the gastrocolonic mesentery were found. After 6 courses of S-1 plus cisplatin(SP)therapy were performed, the tumor shrank and lymph node swelling and nodule disappearance were observed. Laparotomy and pyloric gastrectomy, partial liver resection, D2 dissection, and Roux-en-Y reconstruction were performed. As a result of histopathological examination, R0 was resected. After the operation, S-1 was taken orally for 1 year, and no recurrence or metastasis has been observed 6 and a half years after the operation. This time, we report a valuable case in which SP therapy was successful for unresectable gastric cancer and long-term survival was obtained by conversion surgery.


Assuntos
Neoplasias Gástricas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino , Combinação de Medicamentos , Gastrectomia , Humanos , Excisão de Linfonodo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgia
8.
Dysphagia ; 34(4): 592-599, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31037328

RESUMO

Swallowing difficulty is among the major complications that can occur after surgery for thoracic esophageal cancer. Recurrent laryngeal nerve paralysis (RLNP) has been considered the most significant cause of a postoperative swallowing difficulty, but association between the two has not been adequately explained. We investigated the relation between postoperative RLNP and swallowing difficulty by means of video fluoroscopy. Our study included 32 patients who underwent subtotal esophagectomy for thoracic esophageal cancer at St. Marianna University School of Medicine between April 2014 and March 2017. We evaluated patients' age and sex, disease stage, preoperative presence of a swallowing difficulty, nutritional status, extent and duration of surgery, blood loss volume, and postoperative presence of RLNP and/or hoarseness. Patients were divided into two groups according to whether oral food intake was possible when video fluoroscopy was performed on postoperative day (POD) 7, and we analyzed the associated factors. Postoperative RLNP occurred in 21 patients (65.6%); hoarseness occurred in 19 (59.4%). Eleven patients (34.4%) suffered swallowing difficulty that prevented food intake. No significant association was found between postoperative swallowing difficulty and postoperative RLNP or hoarseness, but a significant relation was found between the prognostic nutritional index and intraoperative lymph node dissection. Multivariable analysis revealed a significant relation between postoperative swallowing difficulty and only one factor: cervical lymph node dissection (P = 0.0075). There appears to be no relation between RLNP pursuant to esophageal cancer surgery and swallowing difficulty that prevents oral food intake.


Assuntos
Transtornos de Deglutição/etiologia , Neoplasias Esofágicas/cirurgia , Transtornos da Alimentação e da Ingestão de Alimentos/etiologia , Idoso , Idoso de 80 Anos ou mais , Deglutição , Ingestão de Alimentos , Neoplasias Esofágicas/complicações , Esofagectomia/efeitos adversos , Esôfago/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
9.
Esophagus ; 15(2): 88-94, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29892931

RESUMO

BACKGROUND: Esophagogastric anastomosis performed after esophagectomy is technically complex and often the source of postoperative complications. The best technique for this anastomosis remains a matter of debate. We describe a new all-stapled side-to-side anastomosis, which we refer to as triple-stapled quadrilateral anastomosis (TRIQ), that can be performed after minimally invasive surgery, and we report results of a retrospective evaluation of postoperative outcomes among the 60 patients in whom this anastomosis has been performed thus far. METHODS: The anastomosis is created by apposition of the posterior walls of the esophagus and stomach. A linear stapler is applied to create a V-shaped posterior anastomotic wall. The anterior wall is closed in a gentle chevron-like shape with the use of 2 separate linear staplers, resulting in a wide quadrilateral anastomosis. The anastomosis is then wrapped with a greater omentum flap. RESULTS: The patient group comprised 48 men and 12 women with a mean age of 67.8 years. Neoadjuvant chemotherapy was performed in 43 of these patients. Neither the thoracoscopic or laparoscopic procedure was converted to open surgery in any patient. The median operation time was 474 min (range 680-320 min). The intraoperative blood loss volume was 104.4 mL (range 240-30 mL). There were no anastomosis-related complications above Clavien-Dindo grade II. CONCLUSIONS: TRIQ can be performed easily and safely, and good short-term outcome can be expected.


Assuntos
Neoplasias Esofágicas/cirurgia , Esôfago/cirurgia , Estômago/cirurgia , Grampeamento Cirúrgico/métodos , Idoso , Anastomose Cirúrgica/efeitos adversos , Anastomose Cirúrgica/métodos , Perda Sanguínea Cirúrgica , Esofagectomia , Feminino , Humanos , Laparotomia , Masculino , Pessoa de Meia-Idade , Omento/transplante , Duração da Cirurgia , Estudos Retrospectivos , Retalhos Cirúrgicos , Toracoscopia
10.
Surg Endosc ; 32(9): 4011-4016, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29915985

RESUMO

BACKGROUND: Billroth I reconstruction is a means of anastomosis that is widely performed after surgical resection for distal gastric cancer. Interest has grown in totally laparoscopic gastrectomy, and several methods for totally laparoscopic performance of Billroth I reconstruction have been reported. However, the methods are cumbersome, and postoperative complications such as twisting at the site of anastomosis and obstruction due to stenosis have arisen. We developed an augmented rectangle technique (ART) by which the anastomosis is created laparoscopically with the use of three automatic endoscopic linear staplers, and the resulting anastomotic opening is wide and less likely to become twisted or stenosed. The technical details of our ART-based Billroth I anastomosis are presented herein along with results of the procedure to date. METHODS: The technique was applied in 160 patients who underwent totally laparoscopic distal gastrectomy for gastric cancer between December 2013 and August 2017. Clinicopathological data, surgical data, and postoperative outcomes were analyzed. RESULTS: During surgery, there were no troubles associated with gastrointestinal reconstruction and there was no transition to laparotomy. There were no postoperative complications, including suture failure and stenosis, associated with the gastrointestinal reconstruction, and the average postoperative hospital stay was 12 days. CONCLUSION: Totally laparoscopic ART-based Billroth I reconstruction is both feasible and safe. We expect this technique to contribute to the spread of safe totally laparoscopic surgery for gastric cancer.


Assuntos
Gastrectomia/métodos , Gastroenterostomia/métodos , Laparoscopia/métodos , Neoplasias Gástricas/cirurgia , Idoso , Feminino , Humanos , Masculino
11.
Gan To Kagaku Ryoho ; 45(4): 658-660, 2018 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-29650826

RESUMO

A 55-year-old man underwent distal gastrectomy and D2 lymph node dissection for type 2 gastric cancer of the antrum. One year later, CEA elevation was discovered, and contrast-enhanced abdominal computed tomography(CT)revealed a 40 mm mass in the liver(S8), which was judged to be a metastatic recurrence of the gastric cancer.S -1 plus CDDP was administered in 5 courses, followed by regular treatment with S-1 alone.Two years after the recurrence was diagnosed, the patient's CEA level was found to be normal, and CT revealed almost total scarring.After 2 more years, there was still no sign of recurrence, so, with the patient's consent, we discontinued the chemotherapy.Eight years after the gastrectomy, a 10mm nodular shadow was observed in the left lower lung lobe, and resection was performed.Despite the earlier diagnosis of gastric adenocarcinoma, this mass was considered a primary lung adenocarcinoma, and the patient died of small-cell lung cancer 11 years and 8 months after the gastrectomy.It is notable that the liver metastasis in this case responded to the S-1 plus CDDP and S-1 therapies, and this response is considered in light of the literature.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Antimetabólitos Antineoplásicos/uso terapêutico , Cisplatino/administração & dosagem , Combinação de Medicamentos , Gastrectomia , Humanos , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Ácido Oxônico/uso terapêutico , Recidiva , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Tegafur/uso terapêutico
12.
Mol Cell Biol ; 30(16): 3981-93, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20547751

RESUMO

The ever-expanding knowledge of the role of p53 in cellular metabolism, apoptosis, and cell cycle control has led to increasing interest in defining the stress response pathways that regulate Mdm2. In an effort to identify novel Mdm2 binding partners, we performed a large-scale immunoprecipitation of Mdm2 in the osteosarcoma U2OS cell line. One significant binding protein identified was Hep27, a member of the short-chain alcohol dehydrogenase/reductase (SDR) family of enzymes. Here, we demonstrate that the Hep27 preprotein contains an N-terminal mitochondrial targeting signal that is cleaved following mitochondrial import, resulting in mitochondrial matrix accumulation of mature Hep27. A fraction of the mitochondrial Hep27 translocates to the nucleus, where it binds to Mdm2 in the central domain, resulting in the attenuation of Mdm2-mediated p53 degradation. In addition, Hep27 is regulated at the transcriptional level by the proto-oncogene c-Myb and is required for c-Myb-induced p53 stabilization. Breast cancer gene expression analysis correlated estrogen receptor (ER) status with Hep27 expression and p53 function, providing a potential in vivo link between estrogen receptor signaling and p53 activity. Our data demonstrate a unique c-Myb-Hep27-Mdm2-p53 mitochondria-to-nucleus signaling pathway that may have functional significance for ER-positive breast cancers.


Assuntos
Oxirredutases do Álcool/genética , Oxirredutases do Álcool/metabolismo , Genes myb , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Oxirredutases do Álcool/antagonistas & inibidores , Sequência de Bases , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carbonil Redutase (NADPH) , Linhagem Celular , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Feminino , Humanos , Técnicas In Vitro , Microscopia Imunoeletrônica , Mitocôndrias/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Ligação Proteica , Estabilidade Proteica , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Interferência de RNA , RNA Interferente Pequeno/genética , Receptores de Estrogênio/metabolismo , Transdução de Sinais
13.
Surg Today ; 40(4): 380-4, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20339996

RESUMO

The patient was a 75-year-old asymptomatic man, in whom a tumor mass in the pancreatic tail had been found 6 months earlier. Computed tomography revealed a mass 7 cm in diameter, and an enhancement with contrast medium was observed at the periphery and partially inside the mass, but not in most parts of the tumor. Endoscopic retrograde cholangiopancreatography showed a filling defect in the main pancreatic duct. A distal pancreatectomy was performed because of the possibility of a malignant tumor. The tumor consisted of a lobular invasive growth component and a component with intraductal growth into the main pancreatic duct, and histologically the tumor cells had solid acinar to partially trabecular/tubular patterns. Trypsin (an acinic cell marker) expression was widely observed, followed by the expression of chromogranin A (an endocrine cell marker) in about 30% of the tumor cells. The tumor was diagnosed as mixed acinar-endocrine carcinoma according to the WHO classification.


Assuntos
Carcinoma de Células Acinares/patologia , Neoplasias das Glândulas Endócrinas/patologia , Ductos Pancreáticos/patologia , Neoplasias Pancreáticas/patologia , Idoso , Biomarcadores/análise , Colangiopancreatografia Retrógrada Endoscópica , Cromogranina A/análise , Humanos , Masculino , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia Computadorizada por Raios X
15.
Gan To Kagaku Ryoho ; 36(4): 667-70, 2009 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-19381045

RESUMO

A 78-year old man underwent low anterior resection for Stage IIIb rectal cancer(Ra). After surgery, he underwent the Roswell Park Memorial Institute(RPMI)regimen for 6 months followed by oral UFT for 8 months. Since liver metastasis(S6)recurred 2 years and 2 months after surgery, he underwent S6 subsegmentectomy. Four years and 4 months later, he developed multiple lymph node metastases(the Virchow, paraaortic, and intrapelvic lymph nodes), for which FOLFIRI therapy was started, but converted to the RPMI regimen because of strong gastrointestinal side effects. After 3 courses of this regimen, tumor markers returned to normal, and imaging studies showed that the metastases had disappeared. This was interpreted as a complete response(CR). The patient has maintained the complete response for 1 year and 4 months since the start of the RPMI regimen.


Assuntos
Antineoplásicos/uso terapêutico , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Idoso , Biomarcadores Tumorais/sangue , Humanos , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Masculino , Tomografia por Emissão de Pósitrons , Neoplasias Retais/sangue , Neoplasias Retais/cirurgia , Indução de Remissão , Tomografia Computadorizada por Raios X
16.
World J Surg Oncol ; 5: 59, 2007 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-17540038

RESUMO

BACKGROUND: We report an extremely rare case of concomitant huge exophytic GIST of the stomach and Kasabach-Merritt phenomenon (KMP). CASE PRESENTATION: The patient was a 67-year-old man experiencing abdominal distension since September 2006. A physical examination revealed a 25 x 30 cm hard mass that was palpable in the middle and lower left abdomen minimal intrinsic mobility and massive ascites. Since the admitted patient was diagnosed with DIC, surgery could not be performed. The patient received a platelet transfusion and the DIC was treated. Due to this treatment, the platelet count recovered to 7.0 x 10(4); tumor resection was performed at 16 days after admission. Laparotomy revealed a huge extraluminal tumor arising from the greater curvature of the stomach that measured 25 x 30 cm and had not ruptured into the peritoneal cavity or infiltrated other organs. Partial gastric resection was performed. The resected mass measured 25 x 25 x 20 cm. In cross section, the tumor appeared hard and homogenous with a small polycystic area. Histopathology of the resected specimen showed large spindle cell GIST with >5/50 HPF (high-power field) mitotic activity. The postoperative course was uneventful, and the coagulopathy improved rapidly. CONCLUSION: Since the characteristic of tumor in this case was hypervascularity with bleeding and necrotic lesions, coagulopathy was thought to be caused by the trapping of platelets within a large vasculized tumor mass.


Assuntos
Coagulação Intravascular Disseminada/complicações , Tumores do Estroma Gastrointestinal/complicações , Neoplasias Gástricas/complicações , Coagulação Intravascular Disseminada/terapia , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/patologia
17.
J Biol Chem ; 281(27): 18463-72, 2006 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-16679321

RESUMO

How cells coordinate inhibition of growth and division during genotoxic events is fundamental to our understanding of the origin of cancer. Despite increasing interest and extensive study, the mechanisms that link regulation of DNA synthesis and ribosomal biogenesis remain elusive. Recently, the tumor suppressor p14(ARF) (ARF) has been shown to interact functionally with the nucleolar protein B23/NPM (B23) and inhibit rRNA biogenesis. However, the molecular basis of the ARF-B23 interaction is hitherto unclear. Here we show that a highly conserved motif in the B23 oligomerization domain is essential for mediating ARF binding in vivo. Mutagenesis of conserved B23 core residues (L102A, G105A, G107A) prevented B23 from interacting with ARF. Modeling of the B23 core indicated that substitutions in the GSGP loop motif could trigger conformational changes in B23 thereby obstructing ARF binding. Interestingly, the GSGP loop mutants were unstable, defective for oligomerization, and delocalized from the nucleolus to the nucleoplasm. B23 core mutants displayed increased ubiquitination and proteasomal degradation. We conclude that the functional integrity of the B23 core motif is required for stability, efficient nucleolar localization as well as ARF binding.


Assuntos
Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Proteína Supressora de Tumor p14ARF/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação/genética , Linhagem Celular Tumoral , Replicação do DNA/fisiologia , Dimerização , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Proteínas Nucleares/genética , Nucleofosmina , Ligação Proteica , Conformação Proteica , Estrutura Terciária de Proteína , RNA Ribossômico/fisiologia , Alinhamento de Sequência , Relação Estrutura-Atividade
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