Elevated susceptibility of the p53 knockout mouse esophagus to methyl-N-amylnitrosamine carcinogenesis

Shirai, Norimitsu; Tsukamoto, Tetsuya; Yamamoto, Masami; Iidaka, Takeshi; Sakai, Hiroki; Yanai, Tokuma; Masegi, Toshiaki; Donehower, Lawrence A.; Tatematsu, Masae

doi:10.1093/carcin/23.9.1541

Cited by 21 publications

(27 citation statements)

References 36 publications

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“…Although tumour suppression by p53 is tissue type-dependent, a decrease in dosage of the p53 gene has been shown to promote carcinogen-induced tumorigenesis at many sites, 34,35 including skin, 36 bladder, 37 lung, 38 salivary gland 39 and oesophagus. 40 These studies have shown that p53 is important in controlling early events in oncogenesis in these tissues, but it has not been clear until now that this also applied to colon.…”

Section: Discussionmentioning

confidence: 99%

Absence of acute apoptotic response to genotoxic carcinogens in p53‐deficient mice is associated with increased susceptibility to azoxymethane‐induced colon tumours

Ying

Leu

Young

2005

Intl Journal of Cancer

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Acute apoptotic response to genotoxic carcinogens (AARGC) might be important for controlling the consequences of mutational load in the colon. It has been shown to occur in parallel with activation of DNA repair mechanisms. Inadequate AARGC might allow development of mutated clones with the potential to progress to cancer. In this study, we tested if p53 levels were important for AARGC in the colon and whether defective AARGC was associated with increased risk for colorectal oncogenesis. Apoptosis was measured in colonic epithelium of mice from each p53 genotype ( p53 -/-, p53 +/-, wild-type) without and 8 hr following a single injection of azoxymethane (AOM). To determine risk for carcinogen-induced colorectal cancer (CRC), groups of mice from each p53 genotype received 3 weekly injections of AOM and colons were examined for tumour 20 weeks later. Rates of spontaneous apoptosis in colon were not affected by p53 level. However, AARGC was absent in p53 -/-mice and reduced by 50% in p53 +/-mice (both p < 0.01) compared to wild-type mice. AOM induced tumours in 30% of wild-type mice (average multiplicity 1.0 tumours/mouse) compared to 72% of p53 +/-mice (2.0 tumours/ mouse, p < 0.01) and 100% of p53 -/-mice (2.8 tumours/mouse, p < 0.01). Without AOM, significantly fewer mice in all groups had tumours. Rates of apoptosis in tumours were independent of p53 status. p53 dysfunction puts intestinal epithelia at increased risk of genotoxin-induced oncogenesis due to impairment of apoptotic response mechanisms. p53 levels do not appear, however, to be important for spontaneous apoptosis in normal epithelium or apoptosis in tumours. Subsequent studies are now warranted to test the converse, namely, that enhanced apoptotic response to carcinogen reduces risk for colorectal oncogenesis. ' 2005 Wiley-Liss, Inc.Key words: apoptosis; carcinogen; intestinal epithelia; colorectal cancer; p53Clinical and animal studies indicate that CRC development is characterized by progressive genomic instability with multiple genetic alterations. p53 is commonly affected as >50% of CRCs show abnormality in both alleles. p53 plays an important role by recognizing DNA damage, triggering repair and apoptosis and inducing cell cycle arrest. It maintains genomic stability and prevents accumulation of multiple genetic changes characteristic of the development of neoplasia. 1 Attenuated apoptosis and accelerated tumour growth correlate with loss of p53, suggesting that loss of p53-mediated apoptosis is the rate-limiting step in tumour progression. 2,3 Whether p53 is important in regulating genetic events early in oncogenesis, such as initiating mutations, is unclear.Genotoxic carcinogens such as AOM are colorectum-selective carcinogens in rodents that alkylate DNA and initiate oncogenesis by forming DNA adducts. 4 Initiating events such as these may be relevant for humans as mutations consistent with alkylating genotoxin-induced damage have been described in human gastrointestinal tissues 5 and specifically in K-ras and p53. [6][7][8] In response to ...

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Section: Discussionmentioning

confidence: 99%

Absence of acute apoptotic response to genotoxic carcinogens in p53‐deficient mice is associated with increased susceptibility to azoxymethane‐induced colon tumours

Ying

Leu

Young

2005

Intl Journal of Cancer

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“…Several reports have described the pattern of progression from normal mucous to dysplasia, to carcinoma in situ (Shi et al, 1999;Saeki et al, 2002;Shirai et al, 2002). Oesophageal dysplasia is also believed to be one of the precursors for OSCC.…”

Section: Discussionmentioning

confidence: 99%

DARPP-32 expression arises after a phase of dysplasia in oesophageal squamous cell carcinoma

et al. 2004

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This is the first report to correlate DARPP-32 immunoreactivity (dopamine and cAMP-regulated phosphoprotein, M r 32 000) to clinicopathological status in human cancer. DARPP-32 is recognised as a neuronal protein. A recent study demonstrated that DARPP-32, and a truncated isoform t-DARPP, are overexpressed in gastric carcinoma during the process of carcinogenesis. The biological function of DARPP-32, however, is still unclear. The purpose of this study was to clarify the roles of DARPP-32 and t-DARPP in oesophageal squamous cell carcinoma (OSCC). Initially, we investigated DARPP-32 and t-DARPP expression in OSCC cell lines by Reverse transcription -polymerase chain reaction and Western blot. DARPP-32 expression was observed in four out of seven (57.1%) cell lines, but t-DARPP expression was not observed in any cell lines. In oesophageal tissue sample, DARPP-32 expression was observed in four out of seven (57.1%) tumour tissues, while t-DARPP was not observed in any tissues. Subsequently, DARPP expression was assessed by immunohistochemistry, using a polyclonal antibody, in tissue sections from 122 patients with primary OSCC. DARPP immunoreactivity was not observed in any normal oesophageal mucous membranes. On the other hand, positive DARPP immunostaining was detected in 37 patients (30.3%) and correlated inversely with pathologic stage (P ¼ 0.0284), pT (P ¼ 0.0438), pN (P ¼ 0.0303) and tumour size (P ¼ 0.012). The overall survival rate was worse in patients with DARPP-negative tumours than in patients with DARPP-positive tumours (P ¼ 0.0453). Interestingly, DARPP expression was observed in only one out of 45 cases of dysplasia. These observations suggest that DARPP-32 (rather than t-DARPP) expression arises after a phase of dysplasia in OSCC, and that tumours expressing DARPP-32 progress less rapidly than DARPP-32-negative tumours.

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“…The phosphorylation status of p53 determines the stability of the protein and controls cell cycle progression, which serves as a master-switch for promoting apoptosis (Ginsberg et al, 1991;Ashcroft and Vousden, 1999;Colman et al, 2000;Asher et al, 2001;Sogame et al, 2003). Alterations of p53 protein, such as missense mutations and loss of its expression caused by nonsense or frame-shift mutations, can result in carcinogenesis (Hussain and Harris, 1998;Medina et al, 2002;Shirai et al, 2002;Nishikawa et al, 2003;Hofseth et al, 2004).…”

Section: Role Of P53 In Uv Irradiation-induced Dna Damagementioning

confidence: 99%

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

2006

Progress in Retinal and Eye Research

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One of the functional roles of the corneal epithelial layer is to protect the cornea, lens and other underlying ocular structures from damages caused by environmental insults. It is important for corneal epithelial cells to maintain this function by undergoing continuous renewal through a dynamic process of wound healing. Previous studies in corneal epithelial cells have provided substantial evidence showing that environmental insults, such as ultraviolet (UV) irradiation and other biohazards, can induce stress-related cellular responses resulting in apoptosis and thus interrupt the dynamic process of wound healing. We found that UV irradiation-induced apoptotic effects in corneal epithelial cells are started by the hyperactivation of K + channels in the cell membrane resulting in a fast loss of intracellular K + ions. Recent studies provide further evidence indicating that these complex responses in corneal epithelial cells are resulted from the activation of stressrelated signaling pathways mediated by K + channel activity. The effect of UV irradiation on corneal epithelial cell fate shares common signaling mechanisms involving the activation of intracellular responses that are often activated by the stimulation of various cytokines. One piece of evidence for making this distinction is that at early times UV irradiation activates a Kv3.4 channel in corneal epithelial cells to elicit activation of c-Jun N-terminal kinase cascades and p53 activation leading to cell cycle arrest and apoptosis. The hypothetic model is that UV-induced potassium channel hyperactivity as an early event initiates fast cell shrinkages due to the loss of intracellular potassium, resulting in the activation of scaffolding protein kinases and cytoskeleton reorganizations. This review article presents important control mechanisms that determine Kv channel activity-mediated cellular responses in corneal epithelial cells, involving activation of stress-induced signaling pathways, arrests of cell cycle progression and/or induction of apoptosis.

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Elevated susceptibility of the p53 knockout mouse esophagus to methyl-N-amylnitrosamine carcinogenesis

Cited by 21 publications

References 36 publications

Absence of acute apoptotic response to genotoxic carcinogens in p53‐deficient mice is associated with increased susceptibility to azoxymethane‐induced colon tumours

Absence of acute apoptotic response to genotoxic carcinogens in p53‐deficient mice is associated with increased susceptibility to azoxymethane‐induced colon tumours

DARPP-32 expression arises after a phase of dysplasia in oesophageal squamous cell carcinoma

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

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