Reference SummaryUlanet DB, PLoS One 2010;5(8):e12454
Title |
Loss of p19(Arf) facilitates the angiogenic switch and tumor initiation in a multi-stage cancer model via p53-dependent and independent mechanisms. |
Authors |
Ulanet DB; Hanahan D |
Journal |
PLoS One |
Volume |
5 |
Issue |
8 |
Year |
2010 |
Pages |
e12454 |
Abstract |
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. |
Links |
J:164020 – MGI References 20805995 – National Library of Medicine/PubMed |
| Strain | Model Name | Treatment Agent(s) | Organ Affected | Frequency | Model Details |
|---|---|---|---|---|---|
| B6.Cg-Tg(RIP1-Tag)2Dh | Pancreas - Islet of Langerhans hyperplasia | Pancreas - Islet of Langerhans |
observed |
||
| C57BL/6-Tg(RIP1-Tag)2Dh | Pancreas - Islet of Langerhans hyperplasia | Pancreas - Islet of Langerhans |
high - very high |
||
| C57BL/6-Cdkn2atm1Cjs/+ Tg(RIP1-Tag)2Dh | Pancreas - Islet of Langerhans hyperplasia | Pancreas - Islet of Langerhans |
very high |
||
| C57BL/6-Cdkn2atm1Cjs Tg(RIP1-Tag)2Dh | Pancreas - Islet of Langerhans hyperplasia | Pancreas - Islet of Langerhans |
high - very high |
||
| B6.Cg-Tg(RIP1-Tag)2Dh | Pancreas - Islet of Langerhans lesion - angiogenic | Pancreas - Islet of Langerhans |
observed |
||
| C57BL/6-Tg(RIP1-Tag)2Dh | Pancreas - Islet of Langerhans lesion - angiogenic | Pancreas - Islet of Langerhans |
observed - very high |
||
| C57BL/6-Cdkn2atm1Cjs/+ Tg(RIP1-Tag)2Dh | Pancreas - Islet of Langerhans lesion - angiogenic | Pancreas - Islet of Langerhans |
very high |
||
| C57BL/6-Cdkn2atm1Cjs Tg(RIP1-Tag)2Dh | Pancreas - Islet of Langerhans lesion - angiogenic | Pancreas - Islet of Langerhans |
observed - very high |
||
| C57BL/6-Tg(RIP1-Tag)2Dh Trp53tm1Tyj | Pancreas - Islet of Langerhans lesion - angiogenic | Pancreas - Islet of Langerhans |
very high |
||
| C57BL/6-Cdkn2atm1Cjs Tg(RIP1-Tag)2Dh Trp53tm1Tyj | Pancreas - Islet of Langerhans lesion - angiogenic | Pancreas - Islet of Langerhans |
very high |
||
| B6.Cg-Tg(RIP1-Tag)2Dh | Pancreas - Islet of Langerhans tumor | Pancreas - Islet of Langerhans |
observed |
||
| C57BL/6-Tg(RIP1-Tag)2Dh | Pancreas - Islet of Langerhans tumor | Pancreas - Islet of Langerhans |
observed - 36 |
||
| C57BL/6-Cdkn2atm1Cjs/+ Tg(RIP1-Tag)2Dh | Pancreas - Islet of Langerhans tumor | Pancreas - Islet of Langerhans |
very high |
||
| C57BL/6-Cdkn2atm1Cjs Tg(RIP1-Tag)2Dh | Pancreas - Islet of Langerhans tumor | Pancreas - Islet of Langerhans |
observed - very high |
||
| C57BL/6-Tg(RIP1-Tag)2Dh Trp53tm1Tyj | Pancreas - Islet of Langerhans tumor | Pancreas - Islet of Langerhans |
observed - very high |
||
| C57BL/6-Cdkn2atm1Cjs Tg(RIP1-Tag)2Dh Trp53tm1Tyj | Pancreas - Islet of Langerhans tumor | Pancreas - Islet of Langerhans |
very high |