Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL-/- clear cell renal carcinoma.

Abstract

Most clear cell renal carcinomas (ccRCCs) are initiated by somatic inactivation of the VHL tumor suppressor gene. The VHL gene product, pVHL, is the substrate recognition unit of an ubiquitin ligase that targets the HIF transcription factor for proteasomal degradation; inappropriate expression of HIF target genes drives renal carcinogenesis. Loss of pVHL is not sufficient, however, to cause ccRCC. Additional cooperating genetic events, including intragenic mutations and copy number alterations, are required. Common examples of the former are loss-of-function mutations of the PBRM1 and BAP1 tumor suppressor genes, which occur in a mutually exclusive manner in ccRCC and define biologically distinct subsets of ccRCC. PBRM1 encodes the Polybromo- and BRG1-associated factors-containing complex (PBAF) chromatin remodeling complex component BRG1-associated factor 180 (BAF180). Here we identified ccRCC lines whose ability to proliferate in vitro and in vivo is sensitive to wild-type BAF180, but not a tumor-associated BAF180 mutant. Biochemical and functional studies linked growth suppression by BAF180 to its ability to form a canonical PBAF complex containing BRG1 that dampens the HIF transcriptional signature.

• Authors: Wenhua Gao, Wei Li, Tengfei Xiao, Xiaole Shirley Liu, William G Kaelin Jr
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 114 Issue 5 Pg. 1027-1032 (01 31 2017) ISSN: 1091-6490 [Electronic] United States
• PMID: 28082722 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• DNA-Binding Proteins
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Neoplasm Proteins
• Nuclear Proteins
• PBRM1 protein, human
• RNA, Small Interfering
• Recombinant Proteins
• Transcription Factors
• Von Hippel-Lindau Tumor Suppressor Protein
• VHL protein, human

Topics

• Animals
• Base Sequence
• Carcinoma, Renal Cell (genetics, metabolism, pathology)
• Cell Line, Tumor
• DNA-Binding Proteins
• Frameshift Mutation
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Heterografts
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (physiology)
• Kidney Neoplasms (genetics, metabolism, pathology)
• Mice, Nude
• Neoplasm Proteins (antagonists & inhibitors, deficiency, genetics, physiology)
• Nuclear Proteins (antagonists & inhibitors, deficiency, genetics, physiology)
• RNA Interference
• RNA, Small Interfering (genetics)
• Recombinant Proteins (metabolism)
• Transcription Factors (antagonists & inhibitors, deficiency, genetics, physiology)
• Transcription, Genetic
• Transcriptome
• Von Hippel-Lindau Tumor Suppressor Protein (genetics)