• Archives of Pharmacal Research
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• 제25권2호
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• pp.208-213
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• 2002

The human polyomavirus JC virus is the etiologic agent of progressive multifocal leukoencephalopathy (PML). As the JC virus early promoter directs cell-specific expression of the viral replication factor large T antigen, transcriptional regulation constitutes a major mechanism of glial tropism in PML. It has been demonstrated that SV4O or JC virus large T antigen interacts with p53 protein and regulates many viral and cellular genes. In this study we founts that p53 represses the JC virus early promoter in both glial and nonglial cells To identify the cis-regulatory elements responsible for p53-mediated repression, deletional and site-directed mutational analyses were performed . Deletion of the enhancer region diminished p53-mediated transcriptional repression. However, point mutations of several transcription factor binding sites in the basal promoter region did not produce any significant changes. In support of this observation, when the enhancer was fused to a heterologous promoter, p53 red reduced the promoter activity about three fold. These results indicate that the enhancer region is important for tole repression of JC virus transcription by p53. Furthermore, coexpression of JC virus T antigen with a p53 protein abolished p53-mediated repression of the JC virus early promoter in non-glial cells, but not in glial cells. This finding suggests that T antigen interacts with p53 and regulates JC virus transcription in a cell-specific manner.

• The Korean Journal of Physiology and Pharmacology
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• 제20권5호
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• pp.487-498
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• 2016

Leptin, an adipokine predominantly produced from adipose tissue, is well known to induce tumor growth. However, underlying molecular mechanisms are not established yet. While p53 has long been well recognized as a potent tumor suppressor gene, accumulating evidence has also indicated its potential role in growth and survival of cancer cells depending on experimental environments. In the present study, we examined if p53 signaling is implicated in leptin-induced growth of cancer cells. Herein, we demonstrated that leptin treatment significantly increased p53 protein expression in both hepatic (HepG2) and breast (MCF-7) cancer cells without significant effect on mRNA expression. Enhanced p53 expression by leptin was mediated via modulation of ubiquitination, in particular ubiquitin specific protease 2 (USP2)-dependent manner. Furthermore, gene silencing of p53 by small interfering RNA (siRNA) suppressed leptin-induced growth of hepatic and breast cancer cells, indicating the role of p53 signaling in tumor growth by leptin. In addition, we also showed that knockdown of p53 restored suppression of caspase-3 activity by leptin through modulating Bax expression and prevented leptin-induced cell cycle progression, implying the involvement of p53 signaling in the regulation of both apoptosis and cell cycle progression in cancer cells treated with leptin. Taken together, the results in the present study demonstrated the potential role of p53 signaling in leptin-induced tumor growth.

• 대한바이러스학회지
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• 제29권4호
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• pp.235-245
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• 1999

HIV-1 Tat, a strong transactivator, is essential for the HIV-1 replication and AIDS progression. The Tat function is markedly inhibited by human p53 anti-oncogene. However, the detail mechanism has not yet been clearly revealed. In our previous report, we have addressed that p53 is unlikely to interact directly with HIV-1 Tat. In the consecutive experiments, Tat-phosphorylation was found to increase in proportional to the amounts of transfected p53. This work was initiated to identify the signaling factor that is involved in the p53-mediated Tat suppression. Several protein kinases were tested for the phosphorylation of Tat, and we found that PKR is likely to be involved in the p53-mediated Tat suppression. PKR was co-immunoprecipitated by anti-Tat antibody in the Tat-expressing Jurkat cell lysates only when the cells were transfected by p53, indicating that PKR-Tat interaction depends on the p53 activity. The interaction seems to result in PKR-mediated Tat-phosphorylation. Tat function was not blocked by p53 when co-transfected trasiently with antisense-PKR. We have generated PKR-knock out Jurkat cell clone. The PKR defective Jurkat cells didn't show the p53-mediated Tat suppression. These data indicate that p53-mediated Tat suppression is strongly associated with PKR. PKR-mediated Tat phosphorylation experiments are now under investigation by kinase assay and co-immunoprecipitation in the presence or absence of p53.

• Asian Pacific Journal of Cancer Prevention
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• 제14권12호
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• pp.7737-7741
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• 2013

Background: Human papilloma virus infection is associated with genesis and malignant potential of cervical cancer. E6 and E7 oncogens are known to bind to p53 and retinoblastoma gene products, abrogating their functions as tumor suppressors, leading to an abnormal cell cycle machinery. Roles of the p53 homolog p63 have also been postulated, E6 expression leading to TAp63b degradation allowing anchorage independent growth. Molecular studies correlated with clinicopathological factors are important to determine prognosis and treatment strategies, but results have been controversial and need to be clarified. Aim: To investigate expression of p53 and p63 in cervical squamous cell carcinomas in correlation with age, FIGO staging, morphology, and cancer cell proliferation. Materials and Methods: Expression of p53 and p63 immunohistochemical staining in a total of 56 paraffin-embedded tissues of cervical squamous cell carcinomas from Dr. Sardjito General Hospital Indonesia, was evaluated for correlation with clinicopathological parameters. The Mann-Whitney test was used to compare the percentage of p53 and p63 expression with patient age, FIGO staging and morphology and to compare mean p53 and p63 expression. The Spearman correlation test was applied to correlate p53 and p63 expression with that of Ki-67. A p-value of <0.05 was considered statistically significant. Results: There were significant associations between p53 expression with age (p=0.019) and FIGO staging (p=0.026), but not with with morphology or Ki-67 expression. There were no links between p63 expression and age, morphology, FIGO staging or Ki-67. Conclusions: This study indicated that p53 has a prognostic value in cervical squamous cell carcinomas given the relation with FIGO staging.

• IMMUNE NETWORK
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• 제1권2호
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• pp.151-161
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• 2001

Background: Inactivation in p53 tumor suppressor gene through a point mutation and deletion is one of the most frequent genetic changes found in human cancer, with 50% of an incidence. This high rate of mutation mostly suggests that the gene plays a central role in the development of cancer and the mutations detected so far were found in exons 5 to 8. Mutation of p53 locus produced accumulation of abnormal p53 protein, and negative regulation of cell proliferation and transcriptional activation as a suppressor of transformation were lost. In addition, inhibition of its normal cellular function of wild-type by mutant is an important step in tumorigenesis. Method: 4 colon cancer cell lines (SNU C1, C2A, C4, C5) were examined for mutation in exons 5 to 8 of the p53 tumor suppressor gene by PCR-SSCP analysis and expression pattern by western blotting and immunoprecipitation. p53-mediated transactivation ability were examined by CAT assay and base substitution of p53 in SNU C2A cell were detected by DNA sequencing. Results: 1) SNU C2A cell and SNU C5 cell were detected mobility shifts each in exon 5 and exon 7 of p53 gene by the PCR-SSCP method, implicating being of p53 mutation. 2) 3 colon cancer cell lines (SNU C1, SNU C2A, SNU C5) expressed wild type and mutant type p53 protein. 3) In northern blot experiment, SNU C2A and SNU C5 cell expressed high level of p53 mRNA. 4) Results of p53-mediated transactivation in colon cancer cell lines by CAT assay represented only SNU C2A cell has transcriptional activity. 5) DNA sequencing in SNU C2A cell showed missense mutation in codon 179 of one allele, histidine to arginine and wild type p53 in the other allele. Conclusion: Colon cancer cell lines showed correlation with mutation in p53 gene and accumulation of abnormal p53 protein. Colon cancer cell SNU C2A retained p53-mediated transactivation as heterozygous p53 with one mutant allele in 179 codon and the other wild-type allele.

• 생명과학회지
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• 제17권6호통권86호
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• pp.778-782
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• 2007

Diphenyleneiodonium (DPI)는 NADPH oxidase 같은 flavoenzymes의 저해제로써 널리 사용되고 있다. 본 연구에서는 인간 대장암 세포주 HCT-116 (wild-type p53)와 HT-29 (p53 mutant) 및 인간 유방암 세포주인 MCF-7(wild-type p53)의 세포성장 과정에서의 DPI의 효과를 살펴보았다. DPI는 농도 및 시간 의존적으로 암세포주의성장을 막았으며 G2/M phase에서 cell cycle arrest를 일으켰다. Cell cycle arrest의 가장 높은 값은 DPI 처리후 12 시간에서 관찰할 수 있었다. 한편 DPI는 아폽토시스 그리고 cell cycle arres 에 관여하는 유전자 발현에 관여하는 p53의 표현을 크게 증가시켰으며, 이는 DPI처리 후 6시간 후 부터 관찰할 수 있었다. 그러나 NADPH oxidase의 조합을 억제하는 catechol 계인 apocynin은 p53의 발현을 유도하지 못하였다. 이것은 DPI에 의해 유도되는 p53의 발현증가는 NADPH oxidase활성의 저해와 관련되어 있지 않다는 것을 의미한다. 결론적으로 DPI는 HCT-116, HCT-15 및 MCF-7 암세포주에서 ROS에 비 의존적으로 wild-type p53 발현의 증가를 유도하며, 이 증가된 p53은 DPI에 의해 유도되는 성장 억제 및 C2/M phase에서의 cell cycle arrset과정의 조절기전에 관여한다는 것을 시사한다.

• Tuberculosis and Respiratory Diseases
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• 제40권4호
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• pp.395-403
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• 1993

연구배경 : 암억제 유전자 p53은 393개의 codon을 가지고, 17번 염색체에 위치하며, 정상세포에서 세포의 성장과 함께 암세포로의 형질전환을 억제하는 것으로 알려져 있다. 그러나 유전자 재배열 또는 점 돌연변이가 일어나 비활성 유전자로 바뀌면, 암억제 기능을 소실하게 되어 암발생 감수성이 높아진다. 돌연변이형 p53유전자의 발현 빈도 및 조직학적 유형에 따른 돌연변이형 p53의 발현양상에 대한 연구를 하여 그 의의를 규명하고저 이 연구를 실시하였다. 방법 : 한국인 정상 폐조직 10예 및 서로 다른 유형의 폐암종 40예(소세포 암종 12예, 비소세폐암종 28예)에서, 암억제 유전자 p53의 발현을 관찰하기 위하여, 돌연변이형 p53(Ab-3), 단세포군 항체와 야생형과 돌연변이형의 혼합형 p53(DO7) 단세포군 항체들을 이용하여, 면역조직화학적 검색을 시도하였다. 결과 : 암억제 유전자 돌연변이형 p53은 정상조직 6예의 기관지상피와 폐포 상피세포에서는 발현되지 않았다. 암억제 유전자 돌연변이형 p53을 시행하였던 폐암종 32예 중 15예(46.9%)의 암세포에서 핵내에 산발적으로 p53유전자가 발현되었으며, 소세포폐암종은 8예 중 3예(37.5%) 그리고 비소세포암종은 24예 중 12예(50.0%) 에서 각각 돌연변이형 p53의 발현이 핵내에서 관찰 되었다. 야생형과 돌연변이형을 다함께 포착하는 혼합형 p53(clone DO7)은 정상인 4예의 폐조직의 기관지 상피 세포 및 폐포 상피세포 핵내 및 소세포폐암종 4예와 비소세포 폐암종 4예를 포함한 총 8예 전예의 핵내에서 균질하게 발현되었다. 결론 : 이와같은 결과는 p53유전자의 돌연 변이형의 발현을 의미하는 것이며, 소세포함종 및 대세포암종에서 돌연변이형 p53유전자의 발현 뿐만 아니라 다른 돌연변이형의 암억제 유전자들이 작용 할 가능성과 함께 또 다른 우성 암유전자들의 영향이 폐암종의 발생에 밀접한 관계가 있을 것으로 추적된다.

• Journal of Gastric Cancer
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• 제6권4호
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• pp.214-220
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• 2006

목적: 종양 억제, 세포 주기 조절 및 세포 고사의 기능과 연관 있는 유전자인 p53은 인간 종양에서 가장 흔히 발견되는 돌연변이 유전자로 알려져 있다. 위암에 있어서 p53의 돌연변이 정도와 생존율 등을 비교하여 각각의 상관관계와 예후 인자로써의 유용성에 대해 알아보고자 하였다. 방법: 1999년 3월부터 2001년 4월까지 경북대학교병원에서 위암으로 수술한 331명 환자의 조직을 이용하여, polymerase chain reaction single-strand conformation polymorphism 방법으로 p53 돌연변이를 확인하고, 환자의 임상 병리학적 인자와의 관계를 비교하였고, 환자의 생존율을 비교하였다. 결과: 전체 331명의 환자들의 조직 중 66예(19.9%)의 조직에서 p53 돌연변이가 관찰되었다. 이들 66예 중에서 exon 5에서 23예, exon 6에서 8예, exon 7에서 21예, exon 8에서 17예의 돌연변이를 보였는데, 이중 3예에서 2개의 exon에 돌연변이(exon 5와 exon 6, exon 6과 exon 7, exon 6과 exon 8)를 보였다 p53 돌연변이는 나이와 성별, 육안형, 병리학적 병기, 조직학적 분류, 종양의 위치에 따라서 차이는 없었으나, 장형 156예 중 36예(23.1%), 미만형 145예 중 19예(13.1%)로 유의한 차이가 있었고(P=0.007), p53 돌연변이에 따른 생존기간은 유의한 차이가 없었다(P=0.632). Exon 5는 장형(9.7%)에서 미만형(2.8%))보다 p53 돌연변이 빈도가 높았고(P=0.024), 림프절 전이가 있는 군에서 림프절 전이가 없는 군보다 p53 돌연변이의 빈도가 유의하게 높았다(25.0% vs 15.6%, P=0.034). 나머지 항목에서는 통계학적으로 유의한 차이가 없었다. 근치적 절제술을 시행한 예에서의 p53 돌연변이에 따른 생존율은 유의한 차이를 보이지 않았다(P=0.704). 결론: p53 돌연변이는 위암 환자의 예후인자로써 가치가 충분하지 않다.

• Journal of Chest Surgery
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• 제36권12호
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• pp.952-960
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• 2003

p53은 cyclin Bl을 통해 세포주기 중 G2-M checkpoint 이행을 조절하는 것으로 알려져 있으며 이것은 p53이 여러 종류의 악성종양의 생성과 진행에 중요한 역할을 하는 것을 암시한다. 본 연구의 목적은 식도 편평세포암 환자에서 세포주기 조절인자인 cyclin Bl과 p53의 역할을 규명하는 데 있다. 대상 및 방법: 46예의 식도 편평세포암 환자에서 채취한 정상 편평상피, 이형성 조직과 암조직에서 면역조직화학검사를 이용하여 cyclin Bl과 p53의 발현을 조사하고 임상병리학적인 인자 및 생존율과의 상관관계를 분석하였다. 결과: 정상상피의 기저층에 있는 몇 개의 세포들에서 cyclin Bl이 발현되었다. Cyclin Bl 양성세포의 범위는 이형성증의 정도가 심해질수록 증가하였다. Cyclin Bl의 양성율은 41.3% (19예/46예)였고 p53의 양성 발현율은 58.7% (27예/46예)였다. 임상병리학적 인자들 중 병기(p<0.05), 식도 주위 림프절 전이(p=0.05), 림프혈관 침범(p<0.05)만이 cyclin Bl의 발현과 관련이 있었고 단변량분석과 다변량분석에서 cyclin Bl의 발현은 예후불량과 관련이 있었다. p53의 발현은 cyclin Bl의 발현과는 상관관계가 있었으나, 임상병리학적 인자들과 예후와는 무관하였다. 결론: 이상의 결과로 cyclin Bl은 식도암의 생성에 관여함을 알 수 있었고 식도 편평세포암 환자에서 cyclin Bl의 발현은 불량한 예후를 나타내며 술 후 보강 항암요법을 시행함으로써 생존율의 향상에 기여할 수 있을 것으로 생각된다.

• 대한두경부종양학회지
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• 제17권2호
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• pp.169-173
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• 2001

Objectives: The p53 tumor suppressor gene encodes a nuclear transcription factor that is critical regulator of cell growth and proliferation through its action in cell-cycle checkpoint control. The wide variety of stressful stmuli which include DNA damage, hypoxia, heat shock, metabolic changes activate the p53 protein, which in turn drives a series of events that culminate either in cell cycle arrest or apoptosis. Mutations of the p53 gene is the most common genetic alteration in human cancer. This gene is altered in approximately 40-60% of head and neck cancers. Whereas the wild-type form of the p53 protein plays a central role in cell-cycle control in response to DNA damage, most of the mutant forms are unable to do so. The high levels of p53 protein expression in tissues are related to the increased cellular proliferative activity and may be associated with the poor clinical outcome. To determine whether the expression of the p53 protein has prognostic significance and is associated with patterns of treatment failure in head and neck squamous cell carcinoma (HNSCC), We analyzed p53 overexpression in 40 cases of HNSCC. Materials and Methods: Immunohistochemical analysis with a monoclonal antibody (DO7) specific for p53 protein was used to detect expression of the protein in formalin-fixed, paraffin-embedded tumor samples from 40 HNSCC. We evaluated p53 protein expression and analyzed the relationship between the p53 overexpression and age, sex, primary tumor site, stage, survival rate, recurrence. All reported P values resulted from two-sided statistical tests. Results: Overexpression of p53 was detected in 20 cases(50%) among 40 cases of HNSCC. The p53 overexpression was not associated with age, sex, primary tumor site, stage, recurrence and survival rate. Conclusions: In our results, p53 was not significant prognostic factor in HNSCC. Based on many previous studies, It is evident that p53 has a certain role in tumorigenesis of HNSCC. So, the further study is needed to evaluate the prognostic significance of p53 in HNSCC.