p53 and its co-activator p300 are inversely regulated in the mouse colon in response to carcinogen

Aizu, Wataru; Guda, Kishore; Nambiar, Prashant R.; Tong, Xin; Thibodeau, Michael; Rosenberg, Daniel W.; Giardina, Charles

doi:10.1016/s0378-4274(03)00221-2

Cited by 12 publications

(8 citation statements)

References 44 publications

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“…6,7 Genotoxic carcinogens induce an acute apoptotic response in the colonic crypt (i.e., AARGC), 12 and p53 increases in colonic crypt cells within the same time frame. 23 Our study showed that p53 is necessary for this acute apoptotic response. Furthermore, levels of p53 are critical as a gene-dosage effect (haploinsufficiency) is apparent in that AARGC is reduced 50% in p53 þ/-mice.…”

Section: Discussionmentioning

confidence: 53%

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: 53%

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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“…Apoptosis has been reported to be induced by a single dose of AOM in rodents and to peak 6 h after injection of a single injection of AOM in mice: expression of p53‐activated p21, ( 24 ) after DNA damage and p53‐regulated Bax, ( 29 ) are increased in a small subpopulation of cells with apoptosis morphology at 6 h after AOM injection. To confirm the occurrence of apoptosis suppression in the TG colonic mucosa, TG mice were injected with a single 15 mg/kg body weight dose of AOM, and their colons were examined histologically at 0, 3, 6, and 12 h after the injection.…”

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confidence: 99%

Plasma membrane‐associated sialidase (NEU3) promotes formation of colonic aberrant crypt foci in azoxymethane‐treated transgenic mice

et al. 2009

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Human plasma membrane-associated sialidase (NEU3) specifically hydrolyzes gangliosides, and it is up-regulated in colon cancer and plays an essential role in the expression of malignant phenotypes. To clarify the role of NEU3 in tumorigenesis in vivo, we examined the susceptibility of NEU3 transgenic mice to induction of colonic aberrant crypt foci (ACF) by azoxymethane. Mice were injected with azoxymethane (i.p., 15 mg/kg/week) for 6 weeks, and 4 weeks later ACF had formed in the NEU3 transgenic mice significantly more than in the control wild-type mice. Enhanced phosphorylation of epidermal growth factor (EGF) receptor, Akt and ERK and up-regulation of Bcl-xL protein were observed in the transgenic colon mucosa, but no changes were found in cell proliferation, suggesting that the increased ACF formation is due to suppression of apoptosis. Immunohistological analysis with anti-cleaved caspase 3 antibody showed an actual reduction in apoptotic cells in the transgenic mucosa at 6 h after the first azoxymethane injection, when apoptosis in the colonic crypt occurs. Consistent with our previous observations of human colon cancer, thin-layer chromatography of the gangliosides from the transgenic colon mucosa revealed decreased GM3 and increased lactosylceramide as compared to those from the control mucosa, probably because of catalysis of gangliosides by NEU3. The results of this study provide the first evidence that NEU3 essentially increases azoxymethane-induced ACF formation in colon mucosa by suppression of apoptosis, possibly via activation of the EGF signaling pathway, and thus indicate that up-regulation of NEU3 is important to the promotion stage of colorectal carcinogenesis in vivo. (Cancer Sci 2009; 100: 588-594) C olorectal carcinogenesis is thought to occur in several steps that lead from normal mucosa to carcinoma. Aberrant crypt foci (ACF) with dilated irregular luminal openings and thicker epithelial linings are the earliest identifiable mucosal abnormalities in carcinogen-treated rodents and in humans harboring colonic cancer lesions. Formation of ACF is thought to be a precursor of colon cancer.(1-3) Epidermal growth factor receptor (EGFR) signaling is activated in human colon ACF, and expression of related molecules, including proliferating cell nuclear antigen (PCNA), tumor growth factor (TGF)-α, EGFR, and cyclo-oxygenase-2 (COX-2), is increased in hyperproliferative ACF.(4) Azoxymethane (AOM), a DNA-alkylating reagent, is often used to induce the formation of ACF in rodents as an experimental model of colonic tumorigenesis in the premalignant phase. AOM is metabolized to methylazoxymethanol by P450 in the liver, and bacterial flora in the intestine activates methylazoxymethanol to methyldiazonium, which exerts colonotropic mutagenicity.(5) In AOM-induced ACF, an increase of c-fos, decrease in c-myc and hexosamidase, and mutation of the k-ras, APC, and β-catenin genes are observed. (6) Sialic acids have been shown to play a role in various biological processes by influencing the conformation of gl...

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“…It has been shown that, following carcinogen treatment, the colonic epithelium undergoes cell growth arrest and apoptosis which facilitate the repair or elimination of genetically damaged cells (42). In particular, in the case of AOM, the maximum apoptotic death rate has been detected 6 h after single AOM injection (43). Therefore, we analyzed the number of apoptotic cells in the colon of C57Bl6 female Cripto +/− and wt mice by TUNEL, 6 h after single AOM injection (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cripto haploinsufficiency affects in vivo colon tumor development

Giorgio

Liguoro

D’Orsi

et al. 2014

International Journal of Oncology

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Colorectal cancer is one of the most common and aggressive cancers arising from alterations in various signaling pathways, such as the WNT, RAS-MAPK, PI3K and transforming growth factor-β (TGF-β) pathways. Cripto (also called Teratocarcinoma-derived growth factor), the original member of the vertebrate EGF-CFC family, plays a key role in all of these pathways and is deeply involved in early embryo development and cancer progression. The role of Cripto in colon and breast cancer, in particular, has been investigated, as it is still not clearly understood. In this article, we provide the first in vivo functional evidence of a role of Cripto in colon cancer development. We analyzed the effect of Cripto haploinsufficiency on colon tumor formation by treating Cripto heterozygous mice with the colonotropic carcinogen azoxymethane (AOM). Of note, in our model system, Cripto haploinsufficiency increased tumorigenesis. Moreover, we revealed a correlation between the differential AOM response found in wt and Cripto+/− mice and the expression levels of glucose regulated protein-78 (Grp78), a heat shock protein required for Cripto signaling pathways. We hypothesize that the balance between Cripto and Grp78 expression levels might be crucial in cancer development and may account for the increased tumorigenesis in Cripto heterozygous mice. In summary, our results highlight the heterogeneous effect of Cripto on tumorigenesis and the consequent high level of complexity in the Cripto regulatory pathway, whose imbalance causes tumors.

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p53 and its co-activator p300 are inversely regulated in the mouse colon in response to carcinogen

Cited by 12 publications

References 44 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

Plasma membrane‐associated sialidase (NEU3) promotes formation of colonic aberrant crypt foci in azoxymethane‐treated transgenic mice

Cripto haploinsufficiency affects in vivo colon tumor development

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