• Environmental Analysis Health and Toxicology
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• v.19 no.3
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• pp.321-326
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• 2004

The study of p53 tumor suppressor protein is one of most important subjects in an environmental toxicology as well as in cancer biology. Generally, p53 has been known to involve the cell cycle regulation and apoptosis by the activation of its target genes such as p21 and bax in a number of cellular stress responses. In addition, associations of p53 with cellular proteins presumably reflect the involvement of p53 in critical cellular processes such as DNA repair. The complex formation of p53 and exogenous proteins such as viral or cellular proteins has been shown in many cases to play important roles in carcinogenic processes against environmental mutagen. Recently, the disruption of p53 protein by oxidative stress has been also reported to have relevance to carcinogenesis. These findings suggested that the maintaining of stability and functional activity of p53 protein was also important aspect to play as a tumor suppressor protein. Therefore, the detection of functional status of p53 proteins might be an effective biomarker for the cancer and human diseases under the environmental toxicologic carcinogen.

• Proceedings of the SCSK Conference
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• 2003.09a
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• pp.338-351
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• 2003

UV radiation is the most dangerous stress factor among permanent environmental impacts on human skin. Consequences of UV exposure are aberrant tissue architecture, alterations in skin cells including functional changes. Nowadays new kinds of outdoor leisure-time activities and changing environmental conditions make the question of sun protection more important than ever. It is necessary to recognize that self-confident consumers do not consider to change their way of life, they demand modern solutions on the basis of new scientific developments. In the past one fundamental principle of cosmetics was the use of physical and organic filter systems against damaging UV-rays. Today new research results demonstrate that natural protecting cell mechanisms can be activated. Suitable biological actives strongly support the protection function not from the surface but from the inside of the cell. A soy seed preparation (SSP) was proven to stimulate natural skin protective functions. The major functions are an increased energy level and the prevention of DNA damage. These functions can I be defined as biological UV protection. The tumor suppressor protein p53 plays a key role in the regulation of DNA repair. p53 must be transferred into the phosphorylated form to work as transcription factor for genes which are regulating the cell cycle or organizing DNA repair. A pretreatment with SSP increases the phosphorylation rate of p53 of chronically UV-irradiated human keratinocytes significantly. According to the same test procedure SSP induces a dramatic increase in the expression of the tumor suppressor protein p14$^{ARF}$ that is supporting the p53 activity by blocking the antagonist of p53, the oncoprotein Mdm2. Mdm2, a ubiquitin E3-ligase, downregulates p53 and at the same time it prevents phosphorylation of p53. The positive influence of the tumor suppressor proteins explains the stimulation of DNA repair and prevention of sunburn cell formation by SSP, which was proven in cell culture experiments. In vivo the increased skin tolerance against UV irradiation by SSP could be confirmed too. We have assumed, that an increased repair potential provides full cell functionality.y.

• BMB Reports
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• v.56 no.10
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• pp.557-562
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• 2023

Dysregulation of the E3 ubiquitin ligase Parkin has been linked to various human cancers, indicating that Parkin is a tumor suppressor protein. However, the mechanisms of action of Parkin remain unclear to date. Thus, we aimed to elucidate the mechanisms of action of Parkin as a tumor suppressor in human lung and colorectal cancer cells. Results showed that Parkin overexpression reduced the viability of A549 human lung cancer cells by inducing G2/M cell cycle arrest. In addition, Parkin caused DNA damage and ATM (Ataxia telangiectasia mutated) activation, which subsequently led to p53 activation. It also induced the p53-mediated upregulation of p21 and downregulation of cyclin B1. Moreover, Parkin suppressed the proliferation of HCT-15 human colorectal cancer cells by a mechanism similar to that in A549 lung cancer cells. Taken together, our results suggest that the tumor-suppressive effects of Parkin on lung and colorectal cancer cells are mediated by DNA damage/p53 activation/cyclin B1 reduction/cell cycle arrest.

• IMMUNE NETWORK
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• v.1 no.2
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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.

• Journal of Chest Surgery
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• v.29 no.11
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• pp.1223-1231
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• 1996

Immunohistochemical stains for RB and p53 tumor suppressor gene products were performed on 72 cases of resected primary lung cancer tissues to study the correlation between their expressions and the histologic types, the clinical stage, and the survival rate. The results were as follows. 1. The RB protein was altered or absent in 38 cases (52.8%), and the mutant p53 protein was detected in 35 cases (48.6%). 2. The incidences of RB and p53 protein expression were significantly different among the histologic types (p＜0.05) but were not correlated with the clinical stages of lung cancer (p＞0.05). 3. The two year survival rate of patients with alteration of both RB and p53 genes (RB-/p53＋) was 22. 4%, and that with no alteration of both genes (RB+/p53-) was 63.1%. This difference was statistically significant (p=0.01). 4. It was shown that alteration of RB protein greatly affects the prognosis of lung carcinoma by multivariate analysis of prognostic factors. The presence or absence of RB and mutant p53 protein in tumor cells is closely related to the survival of primary lung cancer patients, and it is suggested that RB gene expression is an independent prognostic factor of primary lung cancer.

• Animal cells and systems
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• v.6 no.3
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• pp.263-269
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• 2002

The p53 tumor suppressor gene is among the most frequently mutated and studied genes in human cancer, but the mechanisms by which it sur presses tumor formation remain unclear. DNA damage regulates both the protein levels of p53 and its affinity for specific DNA sequences. Stabilization of p53 in response to DNA damage is caused by its dissociation from Mdm2, a downstream target gene of p53 and a protein that targets p53 for degradation in the proteosome. Recent studies have suggested that phosphorylation of human p53 at Ser20 is important for stabilizing p53 in response to DNA damage through disruption of the interaction between Mdm2 and p53. We generated mice with an allele encoding changes at Ser20, known to be essential for p53 accumulation following DNA damage, to enable analyses of p53 stabilization in vivo. Our data showed that the mutant p53 was clearly defective for full stabilization of p53 in response to DNA damage. We concluded that Ser20 phosphorylation is critical for modulating the negative regulation of p53 by Mdm2, probably through phosphorylation-dependent inhibition of p53-Mdm2 interaction in the physiological context.

• BMB Reports
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• v.48 no.2
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• pp.81-90
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• 2015

p73 is a structural and functional homologue of the p53 tumor suppressor protein. Like p53, p73 induces apoptosis and cell cycle arrest and transactivates p53-responsive genes, conferring its tumor suppressive activity. In addition, p73 has unique roles in neuronal development and differentiation. The importance of p73-induced apoptosis lies in its capability to substitute the pro-apoptotic activity of p53 in various human cancer cells in which p53 is mutated or inactive. Despite the great importance of p73-induced apoptosis in cancer therapy, little is known about the molecular basis of p73-induced apoptosis. In this review, we discuss the p73 structures reported to date, detailed structural comparisons between p73 and p53, and current understanding of the transcription-dependent and -independent mechanisms of p73-induced apoptosis.

• Korean Journal of Head & Neck Oncology
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• v.15 no.2
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• pp.141-148
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• 1999

Objectives: The development of thyroid tumor has a relationship with carcinogen, oncogene and tumor suppressor gene. With aminotriazole, radioactive iodine and nitrosomethylurea as carcinogens in rat, authors investigate the incidence in type of the thyroid tumors, p21 and p53 protein expression pattern by immunohistochemical stain and the relationship between the tumors and p21-p53 protein expressions. Materials and Methods: 80 experimental animals were divided into four groups; group 1(control, no carcinogen, n=20), group 2(oral administration of aminotriazole for 36 weeks, n=20), group 3(intraperitoneal injection of 131I for one time and oral administration of aminotriazole for 36 weeks, n=20), group 4(oral administration of nitrosomethylurea for 3 days and aminotriazole for 36 weeks, n=20). After 40 weeks they were sacrificed with pathologic examination and we performed immunohistochemical staining with pan-ras monoclonal antibody for p21 protein and CMI polyclonal antibody for p53 protein with paraffin-embedded specimens. Results: 1) No tumors were observed in group I, but 38.3% of nodular goiters, 11.7% of adenomas and 50.0% of carcinomas were observed in carcinogen treated groups(group 2, 3, 4). 2) The incidence of nodular goiter, adenoma and carcinoma were 70%, 20% and 10% in group 2, 40%, 15% and 45% in group 3 and 5%, 0% and 95% in group 4. 3) p21 protein was not expressed in normal thyroid tissues but was expressed in 26.1% of nodular goiters, 42.9% of adenomas and 6.7% of carcinomas. On the other hands, p53 protein was not expressed in normal thyroid tissues, nodular goiters, adenomas and in well differentiated thyroid carcinomas by immunohistochemical stain. Conclusion: The authors suggest that aminotrizole, 131I, nitrosomethylurea can be etiologic agents in the development of thyroid tumor and the p21 protein can be expressed in the early stage and in benign condition of thyroid tumor but p53 protein is not expressed in all conditions of development in rats.

• Biomolecules & Therapeutics
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• v.31 no.3
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• pp.330-339
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• 2023

Liver kinase B1 (LKB1) is a crucial tumor suppressor involved in various cellular processes, including embryonic development, tumor initiation and progression, cell adhesion, apoptosis, and metabolism. However, the precise mechanisms underlying its functions remain elusive. In this study, we demonstrate that LKB1 interacts directly with malic enzyme 3 (ME3) through the N-terminus of the enzyme and identified the binding regions necessary for this interaction. The binding activity was confirmed to promote the expression of ME3 in an LKB1-dependent manner and was also shown to induce apoptosis activity. Furthermore, LKB1 and ME3 overexpression upregulated the expression of tumour suppressor proteins (p53 and p21) and downregulated the expression of antiapoptotic proteins (nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and B-cell lymphoma 2 (Bcl-2)). Additionally, LKB1 and ME3 enhanced the transcription of p21 and p53 and inhibited the transcription of NF-κB. Moreover, LKB1 and ME3 suppressed the phosphorylation of various components of the phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B signaling pathway. Overall, these results suggest that LKB1 promotes pro-apoptotic activities by inducing ME3 expression.

• IMMUNE NETWORK
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• v.1 no.3
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• pp.221-229
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• 2001

Background: Inactivation of tumor suppressor genes is believed to be important in the development of many human malignancies. Recently, several lines of evidence have indicated that the wild type p53 gene located at 17p13.3, may function as a tumor suppressor gene and that a mutant p53 gene could promote transformation by inactivating normal p53 function in a dominant negative fashion. These broad spectrum of p53 mutation in human cancers provide that mutant p53 and their protein may be potential targets of tumor diagnostic and therapeutic interventions. Method: Colony formation was performed to investigate growth suppressional ability. p53 expression pattern was examined by western blot and p53-mediated transactivation ability was assessed by CAT activity. SNU C2A cells were observed in apoptotic aspects induced by etoposide and $H_2O_2$ treatment, detecting sensitivity on agent, DNA fragmentation through agarose gel, chromatin condensation by fluorescence microscope, and cell cycle distribution by FACS. Result: 1) p53 mutant his179arg ($histidine{\rightarrow}arginine$) detected in SNU C2A cells lost transcriptional activity and growth suppression ability, showing dominant negative effect on its wild type p53. 2) Etoposide-treated SNU C2A cells induced apoptosis, exhibiting dramatic reduction of cell growth, DNA fragmentation, nuclear condensation formation of apoptotic body and increment of sub-G1 cell fraction. 3) Etoposide and $H_2O_2$-treated SNU C2A cells have no high increase of p53 expression and overexpressed p53 protein changed localization, from cytoplasm to nucleus. Also, p53-mediated transcriptional activity was increased by agents-treatment. Conclusion: SNU C2A cells coexpress wild-type and mutant p53 protein induced apoptosis in the condition on DNA damage, through localizational shift from cytoplasm to nucleus of p53 protein rather than the induction of p53 protein. SNU C2A cells derived mutant p53 his179arg abrogated both the growth supression ability and transactivational activity, showing inhibition effect on transcriptional activity of wild type p53, but did not repress the activity of wild type p53 in SNU C2A cells owing to dominant activity of wild type. These cell condition may provide new gene therapeutic implications leading effective antiproliferation of cell when mutant and wild-type p53 protein were co-expressed in cell.