Regulation of translocator protein 18 kDa (TSPO) expression in health and disease states

Abstract

Translocator protein (TSPO) is an 18 kDa high affinity cholesterol- and drug-binding protein found primarily in the outer mitochondrial membrane. Although TSPO is found in many tissue types, it is expressed at the highest levels under normal conditions in tissues that synthesize steroids. TSPO has been associated with cholesterol import into mitochondria, a key function in steroidogenesis, and directly or indirectly with multiple other cellular functions including apoptosis, cell proliferation, differentiation, anion transport, porphyrin transport, heme synthesis, and regulation of mitochondrial function. Aberrant expression of TSPO has been linked to multiple diseases, including cancer, brain injury, neurodegeneration, and ischemia-reperfusion injury. There has been an effort during the last decade to understand the mechanisms regulating tissue- and disease-specific TSPO expression and to identify pharmacological means to control its expression. This review focuses on the current knowledge regarding the chemicals, hormones, and molecular mechanisms regulating Tspo gene expression under physiological conditions in a tissue- and disease-specific manner. The results described here provide evidence that the PKCepsilon-ERK1/2-AP-1/STAT3 signal transduction pathway is the primary regulator of Tspo gene expression in normal and pathological tissues expressing high levels of TSPO.

Figure 1

Hypothetical model for transcriptional regulation of Tspo in hormone- and cAMP- responsive MA-10 Leydig cells, and non-responsive NIH/3T3 fibroblasts. Data presented in this review identified PKCε as the key regulator of Tspo expression. Activation of PKCε, mediated through a MAPK-ERK pathway, targets the AP-1, Ets, and STAT3 transcription factors, whose binding sites are localized to the −805/−515-bp region upstream of the Tspo transcription start site. Ets and Sp1/Sp3 transcription factors play a major role in basal Tspo transcription, and epigenetic modifications of Tspo may also play a role in its expression. Upon activation, PKCε is translocated to the outer mitochondrial membrane, where it interacts with the two primary TSPO-associated proteins VDAC and ANT. Cross-talk between PKC and cAMP-dependent protein kinase (PKA) is possible. Known interactions are denoted by solid lines and hypothetical pathways are denoted by dotted lines.

Figure 2

Tspo gene amplification observed in samples from normal and breast tumor metastasis biopsies. DNA was labeled with biotin-16-dUTP and hybridized to interphase nuclei prepared from human biopsies as previously described (Hardwick et al., 2002). Biotin-labeled DNA was detected using fluorescein-avidin DCS (FITC). Samples from normal and metastatic carcinoma specimens showing two and multiple fluorescence in situ hybridization, respectively, are depicted.