Loss of the Birt-Hogg-Dubé tumor suppressor results in apoptotic resistance due to aberrant TGFß-mediated transcription.
Oncogene
; 30(22): 2534-46, 2011 Jun 02.
Article
em En
| MEDLINE
| ID: mdl-21258407
ABSTRACT
Birt-Hogg-Dubé (BHD) syndrome is an inherited cancer susceptibility disease characterized by skin and kidney tumors, as well as cystic lung disease, which results from loss-of-function mutations in the BHD gene. BHD is also inactivated in a significant fraction of patients with sporadic renal cancers and idiopathic cystic lung disease, and little is known about its mode of action. To investigate the molecular and cellular basis of BHD tumor suppressor activity, we generated mutant Bhd mice and embryonic stem cell lines. BHD-deficient cells exhibited defects in cell-intrinsic apoptosis that correlated with reduced expression of the BH3-only protein Bim, which was similarly observed in all human and murine BHD-related tumors examined. We further demonstrate that Bim deficiency in Bhd(-/-) cells is not a consequence of elevated mTOR or ERK activity, but results instead from reduced Bim transcription associated with a general loss of TGFß-mediated transcription and chromatin modifications. In aggregate, this work identifies a specific tumor suppressive mechanism for BHD in regulating TGFß-dependent transcription and apoptosis, which has implications for the development of targeted therapies.
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Base de dados:
MEDLINE
Assunto principal:
Fator de Crescimento Transformador beta
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Proteínas Proto-Oncogênicas
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Apoptose
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Proteínas Supressoras de Tumor
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Células-Tronco Embrionárias
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Síndrome de Birt-Hogg-Dubé
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article