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 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.
Queensland Institute of Medical Research, Herston, Queensland, Australia. Ian.Tonks@qimr.edu.au
Ian D
ID
Tonks
Arne W
AW
Mould
Wayne A
WA
Schroder
Andrew
A
Cotterill
Nicholas K
NK
Hayward
Graeme J
GJ
Walker
Graham F
GF
Kay
D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D005260:Female; D016158:Genes, p53 / Q000502:physiology*; D007124:Immunoenzyme Techniques; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010673:Pheochromocytoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000502:physiology*; D019076:Transgenes / Q000502:physiology
D002395:Catecholamines; D016160:Retinoblastoma Protein; C045073:Cre recombinase; D019426:Integrases