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Ai Zheng. 2005 Nov;24(11):1398-403.

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[Expression and clinical significance of P53 pathway-associated proteins in pancreatic carcinoma]

[Article in Chinese]

Yu GZ, Zhu MH, Chen Y, Ni CR, Li FM.

Department of Pathology, Changhai Hospital, Shanghai, 200433, PR China.

BACKGROUND & OBJECTIVE: P53 pathway plays a critical role in carcinogenesis of pancreatic carcinoma. However, its trigger and function mechanisms have seldom been reported. This study was to investigate the expression and clinical significance of P53 pathway-related proteins ATM, P53, Mdm2, and P21(WAF/CIP1) in pancreatic carcinoma. METHODS: The expression of ATM, P53, Mdm2, and P21(WAF/CIP1) proteins in 167 specimens of pancreatic carcinoma and 112 specimens of non-cancer pancreatic tissues was detected by tissue microarray and immunohistochemistry. RESULTS: The positive rates of P53 and Mdm2 were higher in pancreatic carcinoma than in non-tumor pancreatic tissues (57.5% vs. 6.3%, 64.1% vs. 5.4%, P < 0.01), while the positive rates of ATM and P21(WAF/CIP1) were lower in pancreatic carcinoma than in non-tumor pancreatic tissues (67.7% vs. 82.1%, 39.5% vs. 71.4%, P < 0.05). ATM expression in pancreatic carcinoma was related to patients' age (P < 0.05). P53 expression was related to tumor differentiation, lymph node metastasis, and nerve involvement (P < 0.05). Mdm2 expression was related to tumor differentiation (P < 0.05). P21(WAF/CIP1) expression was related to patients' age and nerve involvement (P < 0.05). There were statistical correlations between these 4 proteins (P < 0.05). CONCLUSIONS: Overexpression of P53 and Mdm2 and loss of ATM and P21(WAF/CIP1) expression may contribute to the tumorigenesis and development of pancreatic carcinoma. The 4 proteins may affect cell transformation and tumorigenesis through ATM-Mdm2-P53-P21(WAF/CIP1) pathway. Co-detection of P53 and Mdm2 can be used to evaluate the differentiation of pancreatic carcinoma.

PMID: 16552971 [PubMed - in process]

Cancer Sci. 2006 Mar;97(3):226-34.

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Impairment of double-strand breaks repair and aberrant splicing of ATM and MRE11 in leukemia-lymphoma cell lines with microsatellite instability.

Ham MF, Takakuwa T, Luo WJ, Liu A, Horii A, Aozasa K.

Department of Pathology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita-shi, Osaka 565-0871, Japan.

Mutations of DNA double-strand breaks (DSB) repair genes, ATM, MRE11, RAD50, NBS1 and ATR, are postulated to play a role in the development of gastrointestinal malignancies with an impaired mismatch repair (MMR) function. In the present study, mutations of these genes together with the presence of microsatellite instability (MSI) were examined in 50 leukemia-lymphoma cell lines. MSI was detected in 13 (26%) lines. Mutations of intronic mononucleotide repeats in ATM and MRE11 were found in nine and six lines, respectively, whereas mutations of mononucleotide repeats of RAD50 were found in only one line, and none were found in either NBS1 or ATR. Frequencies of ATM and MRE11 mutations were significantly higher in MSI-positive than MSI-negative lines. These mutations generated aberrant splicing in both genes. The intensity of the aberrant transcript of ATM (497del22) was stronger in five lines harboring mononucleotide mutations of 2 bp or more than in the lines without or with a 1-bp mutation. The intensity of the aberrant transcript of MRE11 (315del88) was stronger in four lines with mononucleotide mutations than in lines without. The expression levels of ATM and MRE11 transcripts in MSI-positive lines were significantly higher than those in MSI-negative lines. MSI-positive cell lines showed delay or abrogation of DSB repair. The present study suggests that impairment of the MMR system causes aberrant transcripts in the DSB repair genes ATM and MRE11. This might result in inactivation of the DSB repair system, thus inducing an acceleration of genome instability and accumulation of genetic damage. (Cancer Sci 2006; 97: 226-234).

PMID: 16542220 [PubMed - in process]


Cancer Res. 2006 Mar 15;66(6):2907-12.

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Defective p53 response and apoptosis associated with an ataxia-telangiectasia-like phenotype.

Gueven N, Becherel OJ, Birrell G, Chen P, DelSal G, Carney JP, Grattan-Smith P, Lavin MF.

Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

Ataxia-telangiectasia mutated (ATM), the protein defective in ataxia-telangiectasia, plays a central role in DNA damage response and signaling to cell cycle checkpoints. We describe here a cell line from a patient with an ataxia-telangiectasia-like clinical phenotype defective in the p53 response to radiation but with normal ATM activation and efficient downstream phosphorylation of other ATM substrates. No mutations were detected in ATM cDNA. A normal level of interaction between p53 and peptidyl-prolyl-isomerase Pin1 suggests that posttranslational modification was intact in these cells but operating at reduced level. Defective p53 stabilization was accompanied by defective induction of p53 effector genes and failure to induce apoptosis in response to DNA-damaging agents. Continued association between p53 and murine double minute-2 (Mdm2) occurred in irradiated ATL2ABR cells in response to DNA damage, and incubation with Mdm2 antagonists, nutlins, increased the stabilization of p53 and its transcriptional activity but failed to induce apoptosis. These results suggest that ATM-dependent stabilization of p53 and induction of apoptosis by radiation involve an additional factor(s) that is defective in ATL2ABR cells.

PMID: 16540636 [PubMed - in process]























The ATM protein kinase is a primary activator of the cellular response to DNA double-strand breaks (DSBs). In response to DSBs, ATM is activated and phosphorylates key players in various branches of the DNA damage response network. ATM deficiency causes the genetic disorder ataxia-telangiectasia (A-T), characterized by cerebellar degeneration, immunodeficiency, radiation sensitivity, chromosomal instability and cancer predisposition. The MRN complex, whose core contains the Mre11, Rad50 and Nbs1 proteins, is involved in the initial processing of DSBs. Hypomorphic mutations in the NBS1 and MRE11 genes lead to two other genomic instability disorders: the Nijmegen breakage syndrome (NBS) and A-T like disease (A-TLD), respectively. The order in which ATM and MRN act in the early phase of the DSB response is unclear. Here we show that functional MRN is required for ATM activation, and consequently for timely activation of ATM-mediated pathways. Collectively, these and previous results assign to components of the MRN complex roles upstream and downstream of ATM in the DNA damage response pathway and explain the clinical resemblance between A-T and A-TLD.


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