Differential Expression of p16INK4a in Azoxymethane-Induced Mouse Colon Tumorigenesis

Wang, Qian‐Shu; Παπανικολάου, Αλέξανδρος; Nambiar, Prashant R.; Rosenberg, Daniel W.

doi:10.1002/1098-2744(200007)28:3<139::aid-mc2>3.0.co;2-v

Cited by 20 publications

(17 citation statements)

References 36 publications

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“…As p16 is a potent cell cycle inhibitor and its expression in human colon tumors is associated with reduced markers of cell proliferation, 17,35 p16 might be arresting relatively slowly replicating cells such as stem cells and/or cells experiencing replicative stress and DNA damage. Apoptosis, as judged by caspase 3 activation, was decreased in p16-null tumors, consistent with evidence that p16 can mediate apoptosis in select settings.…”

Section: Discussionmentioning

confidence: 99%

p16Ink4a inhibits histologic progression and angiogenic signaling in min colon tumors

Gibson¹,

Boquoi²,

Chen³

et al. 2005

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 99%

p16Ink4a inhibits histologic progression and angiogenic signaling in min colon tumors

Gibson¹,

Boquoi²,

Chen³

et al. 2005

Cancer Biology & Therapy

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“…21 This model resembles the human idiopathic inflammatory bowel disease, a condition with increased risk for developing cancer. 22 Preneoplastic and neoplastic lesions obtained from these mice covered the whole spectrum of carcinogenesis, ranging from atypical regenerative hyperplasias to adenomas, and adenocarcinomas.…”

Section: Ink4amentioning

confidence: 99%

The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis

et al. 2013

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Oncogenic stimuli trigger the DNA damage response (DDR) and induction of the alternative reading frame (ARF) tumor suppressor, both of which can activate the p53 pathway and provide intrinsic barriers to tumor progression. However, the respective timeframes and signal thresholds for ARF induction and DDR activation during tumorigenesis remain elusive. Here, these issues were addressed by analyses of mouse models of urinary bladder, colon, pancreatic and skin premalignant and malignant lesions. Consistently, ARF expression occurred at a later stage of tumor progression than activation of the DDR or p16INK4A , a tumor-suppressor gene overlapping with ARF. Analogous results were obtained in several human clinical settings, including early and progressive lesions of the urinary bladder, head and neck, skin and pancreas. Mechanistic analyses of epithelial and fibroblast cell models exposed to various oncogenes showed that the delayed upregulation of ARF reflected a requirement for a higher, transcriptionally based threshold of oncogenic stress, elicited by at least two oncogenic 'hits', compared with lower activation threshold for DDR. We propose that relative to DDR activation, ARF provides a complementary and delayed barrier to tumor development, responding to more robust stimuli of escalating oncogenic overload.

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“…The methylating agent azoxymethane (AOM) specifically targets the colon . Genetic modifications found in human colon cancer (Fearon and Vogelstein, 1990) have been identified in carcinogen-treated animals including mutations in K-ras (Vivona et al, 1993), p53 (Okamotu et al, 1995;Singh et al, 1997), Adenomatous polyposis coli (APC) (Maltzman et al, 1997), cyclin D1 (Wang et al, 2000) and the b-catenin protein (Takahashi et al, 2000). To gauge whether CEACAM1 contributes to colon tumor progression in vivo, mice were injected repeatedly with AOM.…”

Section: Ceacam1-deficient Mice Do Not Develop Tumors Spontaneouslymentioning

confidence: 99%

Deletion of the carcinoembryonic antigen-related cell adhesion molecule 1 (Ceacam1) gene contributes to colon tumor progression in a murine model of carcinogenesis

et al. 2006

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Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a glycoprotein that is part of the carcinoembryonic antigen and the immunoglobulin superfamilies. We have shown that it functions as a tumor suppressor and that this function depends upon the presence of the longer CEACAM1 cytoplasmic domain. In this report, we describe the generation of a Ceacam1À/À mouse. The Ceacam1À/À colon exhibits increased in vivo proliferation relative to the wild-type counterpart with a corresponding decreased expression of the p21Cip1 and p27Kip1 Cyclin D kinase inhibitors. The colonic villi undergo decreased apoptosis. Out of 35 litters of mice, no spontaneous tumors in any tissues normally expressing CEACAM1 were found over the lifespan of the animals, suggesting that CEACAM1 may not be involved in initiation of tumor development. However, when mice are treated with azoxymethane to induce colonic tumors, we find that Ceacam1À/À mice developed a significantly greater number of tumors than their littermate controls. Moreover, the tumor size was greater in the knockout mice relative to that in the wild-type mice. These results indicate that deletion of CEACAM1 favors progression of colon tumorigenesis.

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Differential Expression of p16INK4a in Azoxymethane-Induced Mouse Colon Tumorigenesis

Cited by 20 publications

References 36 publications

p16Ink4a inhibits histologic progression and angiogenic signaling in min colon tumors

p16Ink4a inhibits histologic progression and angiogenic signaling in min colon tumors

The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis

Deletion of the carcinoembryonic antigen-related cell adhesion molecule 1 (Ceacam1) gene contributes to colon tumor progression in a murine model of carcinogenesis

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