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Volume 272, Number 51, Issue of December 19, 1997
pp. 32129-32135
(Received for publication, June 10, 1997, and in revised form, August 19, 1997)
From the Departments of To evaluate the role of the mitochondrial
peripheral-type benzodiazepine receptor (PBR) in steroidogenesis, we
developed a molecular approach based on the disruption of the PBR gene,
by homologous recombination, in the constitutive steroid producing R2C
rat Leydig tumor cell line. Inactivation of one allele of the PBR gene
resulted in the suppression of PBR mRNA and ligand binding
expression. Immunoblot and electron microscopic immunogold labeling
analyses confirmed the absence of the 18-kDa PBR protein in the
selected clone. Although mitochondria from the PBR-negative cells
contained high levels of the constitutively expressed 30-kDa steroidogenic activity regulator protein, these cells produced minimal
amounts of steroids compared with normal cells (5%). Moreover, mitochondria from PBR-negative cells failed to produce pregnenolone when supplied with exogenous cholesterol. Addition of the hydrosoluble cholesterol derivative, 22R-hydroxycholesterol, increased
steroid production by the PBR-negative R2C cells, indicating that the cholesterol transport mechanism was impaired. Stable transfection of
the PBR-negative R2C Leydig cells with a vector containing the PBR
cDNA resulted in the recovery of the steroidogenic function of the
cells. These data demonstrate that PBR is an indispensable element of
the steroidogenic machinery, where it mediates the delivery of the
substrate cholesterol to the inner mitochondrial side chain cleavage
cytochrome P-450.
Targeted Disruption of the Peripheral-type Benzodiazepine
Receptor Gene Inhibits Steroidogenesis in the R2C Leydig Tumor Cell
Line
§
,
,
,
,
and
Cell Biology and
§ Pharmacology, Georgetown University Medical Center,
Washington, D. C. 20007
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