Inactivation of SNF5 cooperates with p53 loss to accelerate tumor formation in Snf5(+/-);p53(+/-) mice.
Malignant rhabdoid tumors (MRTs) are poorly differentiated pediatric cancers that arise in various anatomical locations and have a very poor outcome. The large majority of these malignancies are caused by loss of function of the SNF5/INI1 component of the SWI/SNF chromatin remodeling complex. However, the mechanism of tumor development associated with SNF5 loss remains unclear. Multiple studies have demonstrated a role for SNF5 in the regulation of cyclin D1, p16(INK4A), and pRb(f) activities suggesting it functions through the SWI/SNF complex to affect transcription of genes involved in cell cycle control. Previous studies in genetically engineered mouse models (GEMM) have shown that loss of SNF5 on a p53-null background significantly accelerates tumor development. Here, we use established GEMM to further define the relationship between the SNF5 and p53 tumor suppressor pathways. Combined haploinsufficiency of p53 and Snf5 leads to decreased latency for MRTs arising in alternate anatomical locations but not for the standard facial MRTs. We also observed acceleration in the appearance of T-cell lymphomas in the p53(+/-);Snf5(+/-) mice. Our studies suggest that loss of SNF5 activity does not bestow a selective advantage on the p53 spectrum of tumors in the p53(+/-);Snf5(+/-) mice. However, reduced p53 expression specifically accelerated the growth of a subset of MRTs in these mice.
DelBove
Jessica
J
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
Kuwahara
Yasumichi
Y
Mora-Blanco
E Lorena
EL
Godfrey
Virginia
V
Funkhouser
William K
WK
Fletcher
Christopher D M
CD
Van Dyke
Terry
T
Roberts
Charles W M
CW
Weissman
Bernard E
BE
D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000502:physiology*; D005260:Female; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology*; D018335:Rhabdoid Tumor / Q000235:genetics / Q000473:pathology*; D000071796:SMARCB1 Protein; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D000071796:SMARCB1 Protein; C513265:Smarcb1 protein, mouse; D016159:Tumor Suppressor Protein p53
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