The four murine peroxisomal ABC‐transporter genes differ in constitutive, inducible and developmental expression

Abstract

Four ATP-binding cassette (ABC) half-transporters have been identified in mammalian peroxisomes: adrenoleukodystrophy protein (ALDP), adrenoleukodystrophy-related protein (ALDRP), 70-kDa peroxisomal membrane protein (PMP70) and PMP70-related protein (P70R). Inherited defects in ALDP cause the neurodegenerative disorder X-linked adrenoleukodystrophy (X-ALD). By comparative Northern blot analyses we found each of the four murine peroxisomal ABC transporter mRNA species at maximum abundance only in a few tissues, which differed for each family member. The four genes were also regulated differentially during mouse brain development: ALDP mRNA was most abundant in embryonic brain and gradually decreased during maturation; ALDRP and P70R mRNA accumulated in the early postnatal period; and the amount of PMP70 transcript increased slightly during the second and third postnatal week. The different expression patterns could explain why b-oxidation is defective in X-ALD, although ALDRP and PMP70 can replace ALDP functionally in fibroblasts. Dietary fenofibrate had no effect on the ALD and P70R genes, but strongly increased expression of the ALDR and PMP70 genes in mouse liver. However, in P-glycoprotein Mdr1a-deficient mice fenofibrate treatment increased ALDR gene expression also in the brain, suggesting that the multidrug-transporter P-glycoprotein restricts entry of fenofibrate to the brain at the blood±brain barrier. Analysis of the promoter sequences revealed a cryptic nuclear hormone receptor response element of the DR+4 type in the ALDR promoter and a novel 18-bp sequence motif present only in the 5 H flanking DNA of the ALDR and PMP70 genes. The mouse ALDR gene uses a single transcription start site but alternative polyadenylation sites. These data are of importance for the use of ALDP-deficient mice as a model in pharmacological gene therapy studies.Keywords: adrenoleukodystrophy; ATP-binding cassette transporter; fenofibrate; gene expression; peroxisome.Four ABC-transporters have been identified in the mammalian peroxisomal membrane: adrenoleukodystrophy protein (ALDP), adrenoleukodystrophy-related protein (ALDRP), 70 kDa peroxisomal membrane protein (PMP70) and PMP70-related protein (P70R/PMP69). Relative to ALDP the human proteins display 63%, 36%, and 25% amino acid identity [1], respectively, and all have the predicted structure of a half-transporter with one membrane spanning domain and one nucleotide binding fold. As most of the half-transporters identified to date function as dimers, it has been suggested that the peroxisomal ABCtransporters also need to assemble as homo-or heterodimers in order to form a functional unit [2,3].Although the exact functions and substrates of the mammalian peroxisomal ABC-transporters have yet to be defined, the detrimental effects of a deficient transporter is demonstrated by mutations in the ALD gene, leading to the lipid storage disorder X-linked adrenoleukodystrophy (X-ALD, McKusick #300100). Biochemically X-ALD is characterized by defective peroxisomal b-oxidation of sat...

Mouse PeP: A novel peroxisomal protein linked to myoblast differentiation and development

“…This finding is not surprising, because some studies point to a close relationship between peroxisomal enzymatic activity and neuronal growth and myelinogenesis (Lazo et al, 1991;Itoh et al, 2000). Zellweger syndrome and X-linked adrenoleukodystrophy (ALD) are the main examples of the disorders that have promoted the study of the peroxisomal function in the developing brain (Pollard et al, 1995;Berger et al, 1999;Itoh et al, 2000). Liver is another organ where peroxisomes have been extensively studied.…”

Structure-Function Analysis of Peroxisomal ATP-binding Cassette Transporters Using Chimeric Dimers

“…Therefore, it cannot be excluded that heterodimers are functional especially in tissues where at least two ABCD transporters are highly co-expressed. Although expression of ABCD3 is quite ubiquitous, ABCD1 and ABCD2 harbor a tissue-specific but overlapping expression pattern (3,15) characterized by a mirror expression pattern when specific cell types are analyzed (16). Moreover, because ABCD2 expression is highly inducible (17), both ABCD1 and ABCD2 proteins can be found in the same cells and tissues upon stimulation, thus rendering ABCD1/ABCD2 heterodimerization possible.…”

Substrate Specificity Overlap and Interaction between Adrenoleukodystrophy Protein (ALDP/ABCD1) and Adrenoleukodystrophy-related Protein (ALDRP/ABCD2)

“…ALDRP (encoded by the ABCD2 gene (5)), PMP70 (ABCD3 (6)), and PMP69 (ABCD4 (7,8)) cannot be excluded especially in the situation where these proteins are overexpressed. Although a mirror expression pattern is often observed between ALDP and ALDRP when specific cell types are analyzed (9), peroxisomal ABC transporters have overlapping expression patterns rendering possible such interactions (5,10). Coimmunoprecipitation experiments or FRET analysis have demonstrated heterodimerization in cells overexpressing the peroxisomal ABC transporters (11,12).…”