von Hippel-Lindau Protein Induces Hypoxia-regulated Arrest of Tyrosine Hydroxylase Transcript Elongation in Pheochromocytoma Cells

Rat pheochromocytoma (PC12) cells were stably transfected with either wild type or mutated human von Hippel-Lindau tumor suppressor protein (hpVHL). These proteins have opposing effects on regulating expression of the gene encoding tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine...

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Bibliographic Details
Published in:The Journal of biological chemistry 1999-10, Vol.274 (42), p.30109-30114
Main Authors: Kroll, S.L., Paulding, W.R., Schnell, P.O., Barton, M.C., Conaway, J.W., Conaway, R.C., Czyzyk-Krzeska, M.F.
Format: Article
Language:English
Subjects:
Animals
Cell Hypoxia
Down-Regulation
Elongin
elongin A
elongin B
elongin C
Gene Expression Regulation - genetics
Genes, Tumor Suppressor
Humans
Ligases
PC12 Cells
Proteins - genetics
Proteins - metabolism
Proteins - physiology
Rats
RNA, Messenger - genetics
TH gene
Transcription Factors - metabolism
Transfection
Tumor Suppressor Proteins
Tyrosine 3-Monooxygenase - genetics
Ubiquitin-Protein Ligases
VHL protein
Von Hippel-Lindau Tumor Suppressor Protein
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Summary:Rat pheochromocytoma (PC12) cells were stably transfected with either wild type or mutated human von Hippel-Lindau tumor suppressor protein (hpVHL). These proteins have opposing effects on regulating expression of the gene encoding tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. Whereas wild type hpVHL represses levels of TH mRNA and protein 5-fold, a truncated pVHL mutant, pVHL(1–115), induces accumulation of TH mRNA and protein 3-fold. hpVHL-induced inhibition of TH gene expression does not involve either a decrease in TH mRNA stability or repression of TH promoter activity. However, repression results from inhibition of RNA elongation at a downstream region of the TH gene. This elongation pause is accompanied by hpVHL sequestration in the nuclear extracts of elongins B and C, regulatory components of the transcription elongation heterotrimer SIII (elongin A/B/C). Hypoxia, a physiological stimulus for TH gene expression, alleviates the elongation block. A truncated pVHL mutant, pVHL(1–115), stimulates TH gene expression by increasing the efficiency of TH transcript elongation. This is the first report showing pVHL-dependent regulation of specific transcript elongation in vivo, as well as dominant negative activity of pVHL mutants in pheochromocytoma cells.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.274.42.30109