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Loss of p19(Arf) Facilitates the Angiogenic Switch and Tumor Initiation in a Multi-Stage Cancer Model via p53-Dependent and Independent Mechanisms
The Arf tumor suppressor acts as a sensor of oncogenic signals, countering aberrant proliferation in large part via activation of the p53 transcriptional program, though a number of p53-independent functions have been described. Mounting evidence suggests that, in addition to promoting tumorigenesis...
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929208/ https://www.ncbi.nlm.nih.gov/pubmed/20805995 http://dx.doi.org/10.1371/journal.pone.0012454 |
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author | Ulanet, Danielle B. Hanahan, Douglas |
author_facet | Ulanet, Danielle B. Hanahan, Douglas |
author_sort | Ulanet, Danielle B. |
collection | PubMed |
description | The Arf tumor suppressor acts as a sensor of oncogenic signals, countering aberrant proliferation in large part via activation of the p53 transcriptional program, though a number of p53-independent functions have been described. Mounting evidence suggests that, in addition to promoting tumorigenesis via disruptions in the homeostatic balance between cell proliferation and apoptosis of overt cancer cells, genetic alterations leading to tumor suppressor loss of function or oncogene gain of function can also incite tumor development via effects on the tumor microenvironment. In a transgenic mouse model of multi-stage pancreatic neuroendocrine carcinogenesis (PNET) driven by inhibition of the canonical p53 and Rb tumor suppressors with SV40 large T-antigen (Tag), stochastic progression to tumors is limited in part by a requirement for initiation of an angiogenic switch. Despite inhibition of p53 by Tag in this mouse PNET model, concomitant disruption of Arf via genetic knockout resulted in a significantly accelerated pathway to tumor formation that was surprisingly not driven by alterations in tumor cell proliferation or apoptosis, but rather via earlier activation of the angiogenic switch. In the setting of a constitutional p53 gene knockout, loss of Arf also accelerated tumor development, albeit to a lesser degree. These findings demonstrate that Arf loss of function can promote tumorigenesis via facilitating angiogenesis, at least in part, through p53-independent mechanisms. |
format | Text |
id | pubmed-2929208 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-29292082010-08-30 Loss of p19(Arf) Facilitates the Angiogenic Switch and Tumor Initiation in a Multi-Stage Cancer Model via p53-Dependent and Independent Mechanisms Ulanet, Danielle B. Hanahan, Douglas PLoS One Research Article The Arf tumor suppressor acts as a sensor of oncogenic signals, countering aberrant proliferation in large part via activation of the p53 transcriptional program, though a number of p53-independent functions have been described. Mounting evidence suggests that, in addition to promoting tumorigenesis via disruptions in the homeostatic balance between cell proliferation and apoptosis of overt cancer cells, genetic alterations leading to tumor suppressor loss of function or oncogene gain of function can also incite tumor development via effects on the tumor microenvironment. In a transgenic mouse model of multi-stage pancreatic neuroendocrine carcinogenesis (PNET) driven by inhibition of the canonical p53 and Rb tumor suppressors with SV40 large T-antigen (Tag), stochastic progression to tumors is limited in part by a requirement for initiation of an angiogenic switch. Despite inhibition of p53 by Tag in this mouse PNET model, concomitant disruption of Arf via genetic knockout resulted in a significantly accelerated pathway to tumor formation that was surprisingly not driven by alterations in tumor cell proliferation or apoptosis, but rather via earlier activation of the angiogenic switch. In the setting of a constitutional p53 gene knockout, loss of Arf also accelerated tumor development, albeit to a lesser degree. These findings demonstrate that Arf loss of function can promote tumorigenesis via facilitating angiogenesis, at least in part, through p53-independent mechanisms. Public Library of Science 2010-08-27 /pmc/articles/PMC2929208/ /pubmed/20805995 http://dx.doi.org/10.1371/journal.pone.0012454 Text en Ulanet, Hanahan. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Ulanet, Danielle B. Hanahan, Douglas Loss of p19(Arf) Facilitates the Angiogenic Switch and Tumor Initiation in a Multi-Stage Cancer Model via p53-Dependent and Independent Mechanisms |
title | Loss of p19(Arf) Facilitates the Angiogenic Switch and Tumor Initiation in a Multi-Stage Cancer Model via p53-Dependent and Independent Mechanisms |
title_full | Loss of p19(Arf) Facilitates the Angiogenic Switch and Tumor Initiation in a Multi-Stage Cancer Model via p53-Dependent and Independent Mechanisms |
title_fullStr | Loss of p19(Arf) Facilitates the Angiogenic Switch and Tumor Initiation in a Multi-Stage Cancer Model via p53-Dependent and Independent Mechanisms |
title_full_unstemmed | Loss of p19(Arf) Facilitates the Angiogenic Switch and Tumor Initiation in a Multi-Stage Cancer Model via p53-Dependent and Independent Mechanisms |
title_short | Loss of p19(Arf) Facilitates the Angiogenic Switch and Tumor Initiation in a Multi-Stage Cancer Model via p53-Dependent and Independent Mechanisms |
title_sort | loss of p19(arf) facilitates the angiogenic switch and tumor initiation in a multi-stage cancer model via p53-dependent and independent mechanisms |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929208/ https://www.ncbi.nlm.nih.gov/pubmed/20805995 http://dx.doi.org/10.1371/journal.pone.0012454 |
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