[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]
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]
1 q
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.
