Dual Loss of Rb1 and Trp53 in the Adrenal Medulla Leads to Spontaneous Pheochromocytoma
Using a Cre/loxP system, we have determined the phenotypic consequences attributable to in vivo deletion of both Rb1 and Trp53 in the mouse adrenal medulla. The coablation of these two tumor suppressor genes during embryogenesis did not disrupt adrenal gland development but resulted in the neoplast...
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doaj-416ad00bde0c48d59ac534a71f89d5082020-11-25T00:00:41ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022010-03-0112323524310.1593/neo.91646Dual Loss of Rb1 and Trp53 in the Adrenal Medulla Leads to Spontaneous PheochromocytomaIan D. Tonks0Arne W. Mould1Wayne A. Schroder2Andrew Cotterill3Nicholas K. Hayward4Graeme J. Walker5Graham F. Kay6Queensland Institute of Medical Research, Herston, Queensland, AustraliaQueensland Institute of Medical Research, Herston, Queensland, AustraliaQueensland Institute of Medical Research, Herston, Queensland, AustraliaDepartment of Endocrinology and Diabetes, Mater Children's Hospital, Brisbane, Queensland, AustraliaQueensland Institute of Medical Research, Herston, Queensland, AustraliaQueensland Institute of Medical Research, Herston, Queensland, AustraliaQueensland Institute of Medical Research, Herston, Queensland, Australia Using a Cre/loxP system, we have determined the phenotypic consequences attributable to in vivo deletion of both Rb1 and Trp53 in the mouse adrenal medulla. The coablation of these two tumor suppressor genes during embryogenesis did not disrupt adrenal gland development but resulted in the neoplastic transformation of the neural crest-derived adrenal medulla, yielding pheochromocytomas (PCCs) that developed with complete penetrance and were inevitably bilateral. Despite their typically benign status, these PCCs had profound ramifications on mouse vitality, with effected mice having a median survival of only 121 days. Evaluation of these PCCs by both immunohistochemistry and electron microscopy revealed that most Rb1-/-:Trp53-/- chromaffin cells possessed atypical chromagenic vesicles that did not seem capable of appropriately storing synthesized catecholamines. The structural remodeling of the heart in mice harboring Rb1-/-:Trp53-/- PCCs suggests that the mortality of these mice may be attributable to the inappropriate release of catecholamines from the mutated adrenal chromaffin cells. On the basis of the collective data from Rb1 and Trp53 knockout mouse models, it seems that the conversion of Rb1 loss-driven adrenal medulla hyperplasia to PCC can be greatly enhanced by the compound loss of Trp53, whereas the loss of Trp53 alone is generally ineffectual on adrenal chromaffin cell homeostasis. Consequently, the Trp53 tumor suppressor gene is an efficient genetic modifier of Rb1 loss in the development of PCC, and their compound loss in the adrenal medulla has a profound impact on both cellular homeostasis and animal vitality. http://www.sciencedirect.com/science/article/pii/S1476558610801022 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ian D. Tonks Arne W. Mould Wayne A. Schroder Andrew Cotterill Nicholas K. Hayward Graeme J. Walker Graham F. Kay |
spellingShingle |
Ian D. Tonks Arne W. Mould Wayne A. Schroder Andrew Cotterill Nicholas K. Hayward Graeme J. Walker Graham F. Kay Dual Loss of Rb1 and Trp53 in the Adrenal Medulla Leads to Spontaneous Pheochromocytoma Neoplasia: An International Journal for Oncology Research |
author_facet |
Ian D. Tonks Arne W. Mould Wayne A. Schroder Andrew Cotterill Nicholas K. Hayward Graeme J. Walker Graham F. Kay |
author_sort |
Ian D. Tonks |
title |
Dual Loss of Rb1 and Trp53 in the Adrenal Medulla Leads to Spontaneous Pheochromocytoma |
title_short |
Dual Loss of Rb1 and Trp53 in the Adrenal Medulla Leads to Spontaneous Pheochromocytoma |
title_full |
Dual Loss of Rb1 and Trp53 in the Adrenal Medulla Leads to Spontaneous Pheochromocytoma |
title_fullStr |
Dual Loss of Rb1 and Trp53 in the Adrenal Medulla Leads to Spontaneous Pheochromocytoma |
title_full_unstemmed |
Dual Loss of Rb1 and Trp53 in the Adrenal Medulla Leads to Spontaneous Pheochromocytoma |
title_sort |
dual loss of rb1 and trp53 in the adrenal medulla leads to spontaneous pheochromocytoma |
publisher |
Elsevier |
series |
Neoplasia: An International Journal for Oncology Research |
issn |
1476-5586 1522-8002 |
publishDate |
2010-03-01 |
description |
Using a Cre/loxP system, we have determined the phenotypic consequences attributable to in vivo deletion of both Rb1 and Trp53 in the mouse adrenal medulla. The coablation of these two tumor suppressor genes during embryogenesis did not disrupt adrenal gland development but resulted in the neoplastic transformation of the neural crest-derived adrenal medulla, yielding pheochromocytomas (PCCs) that developed with complete penetrance and were inevitably bilateral. Despite their typically benign status, these PCCs had profound ramifications on mouse vitality, with effected mice having a median survival of only 121 days. Evaluation of these PCCs by both immunohistochemistry and electron microscopy revealed that most Rb1-/-:Trp53-/- chromaffin cells possessed atypical chromagenic vesicles that did not seem capable of appropriately storing synthesized catecholamines. The structural remodeling of the heart in mice harboring Rb1-/-:Trp53-/- PCCs suggests that the mortality of these mice may be attributable to the inappropriate release of catecholamines from the mutated adrenal chromaffin cells. On the basis of the collective data from Rb1 and Trp53 knockout mouse models, it seems that the conversion of Rb1 loss-driven adrenal medulla hyperplasia to PCC can be greatly enhanced by the compound loss of Trp53, whereas the loss of Trp53 alone is generally ineffectual on adrenal chromaffin cell homeostasis. Consequently, the Trp53 tumor suppressor gene is an efficient genetic modifier of Rb1 loss in the development of PCC, and their compound loss in the adrenal medulla has a profound impact on both cellular homeostasis and animal vitality.
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url |
http://www.sciencedirect.com/science/article/pii/S1476558610801022 |
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