Genetic variants of human organic anion transporter 4 demonstrate altered transport of endogenous substrates.

Apical reabsorption from the urine has been shown to be important for such processes as the maintenance of critical metabolites in the blood and the excretion of nephrotoxic compounds. The solute carrier (SLC) transporter OAT4 (SLC22A11) is expressed on the apical membrane of renal proximal tubule cells and is known to mediate the transport of a variety of xenobiotic and endogenous organic anions. Functional characterization of genetic variants of apical transporters thought to mediate reabsorption, such as OAT4, may provide insight into the genetic factors influencing the complex pathways involved in drug elimination and metabolite reclamation occurring in the kidney.

Comparison of human solute carriers.

Solute carriers are eukaryotic membrane proteins that control the uptake and efflux of solutes, including essential cellular compounds, environmental toxins, and therapeutic drugs. Solute carriers can share similar structural features despite weak sequence similarities. Identification of sequence relationships among solute carriers is needed to enhance our ability to model individual carriers and to elucidate the molecular mechanisms of their substrate specificity and transport.

Genetic variation in the proximal promoter of ABC and SLC superfamilies: liver and kidney specific expression and promoter activity predict variation.

Membrane transporters play crucial roles in the cellular uptake and efflux of an array of small molecules including nutrients, environmental toxins, and many clinically used drugs. We hypothesized that common genetic variation in the proximal promoter regions of transporter genes contribute to observed variation in drug response. A total of 579 polymorphisms were identified in the proximal promoters (-250 to +50 bp) and flanking 5' sequence of 107 transporters in the ATP Binding Cassette (ABC) and Solute Carrier (SLC) superfamilies in 272 DNA samples from ethnically diverse populations.

Identification and characterization of proximal promoter polymorphisms in the human concentrative nucleoside transporter 2 (SLC28A2).

The human concentrative nucleoside transporter 2 (CNT2) plays an important role in the absorption, disposition, and biological effects of endogenous nucleosides and nucleoside analog drugs. We identified genetic variation in the basal promoter region of CNT2 and characterized the function of the variants. We screened DNA from an ethnically diverse population and identified five basal promoter variants in CNT2.

Organic anion transporter 2 (SLC22A7) is a facilitative transporter of cGMP.

The second messenger, cGMP, mediates a host of cellular responses to various stimuli, resulting in the regulation of many critical physiologic functions. The existence of specific cGMP transporters on the plasma membrane that participate in the regulation of cGMP levels has been suggested in a large number of studies. In this study, we identified a novel plasma membrane transporter for cGMP.

Transcriptional profiling of androgen receptor (AR) mutants suggests instructive and permissive roles of AR signaling in germ cell development.

The androgen receptor (AR) is a transcription factor that plays a critical role in male sexual development, spermatogenesis, and maintenance of hormonal homeostasis. Despite the extensive knowledge of the phenotypic consequences of mutations in Ar, very little is known about the transcriptional targets of AR within the testis. To identify potential targets of androgen signaling in the testis, we have analyzed the transcriptional profile of adult testes from Ar hypomorphs alone or in combination with Sertoli cell-specific Ar ablation.

Organic cation transporters are determinants of oxaliplatin cytotoxicity.

Although the platinum-based anticancer drugs cisplatin, carboplatin, and oxaliplatin have similar DNA-binding properties, only oxaliplatin is active against colorectal tumors. The mechanisms for this tumor specificity of platinum-based compounds are poorly understood but could be related to differences in uptake. This study shows that the human organic cation transporters (OCT) 1 and 2 (SLC22A1 and SLC22A2) markedly increase oxaliplatin, but not cisplatin or carboplatin, accumulation and cytotoxicity in transfected cells, indicating that oxaliplatin is an excellent substrate of these transporters.

Postmeiotic sex chromatin in the male germline of mice.

In mammals, the X and Y chromosomes are subject to meiotic sex chromosome inactivation (MSCI) during prophase I in the male germline, but their status thereafter is currently unclear. An abundance of X-linked spermatogenesis genes has spawned the view that the X must be active . On the other hand, the idea that the imprinted paternal X of the early embryo may be preinactivated by MSCI suggests that silencing may persist longer .

Androgens regulate the permeability of the blood-testis barrier.

Within the mammalian testis, specialized tight junctions between somatic Sertoli cells create basal and apical polarity within the cells, restrict movement of molecules between cells, and separate the seminiferous epithelium into basal and adluminal compartments. These tight junctions form the basis of the blood-testis barrier, a structure whose function and dynamic regulation is poorly understood. In this study, we used microarray gene expression profiling to identify genes with altered transcript levels in a mouse model for conditional androgen insensitivity.

Androgen-regulated transcripts in the neonatal mouse testis as determined through microarray analysis.

Androgens are required for normal spermatogenesis in mammalian testes. These hormones directly regulate testicular somatic cells that, in turn, support germ cell differentiation. However, the identity of genes under androgen regulation in the testis are not well known.

Profiling gene expression during the differentiation and development of the murine embryonic gonad.

The application of microarray technology to the study of mammalian organogenesis can provide greater insights into the steps necessary to elicit a functionally competent tissue. To this end, a temporal profile of gene expression was generated with the purpose of identifying changes in gene expression occurring within the developing male and female embryonic gonad. Gonad tissue was collected from mouse embryos at 11.

Human KIT ligand promoter is positively regulated by HMGA1 in breast and ovarian cancer cells.

KIT ligand (KL) and its receptor, c-kit, are coexpressed in many types of cancer cells and have been implicated in tumor growth and angiogenesis. While Sertoli cell-specific regulation of the KL promoter has been well characterized, regulation in cancer cells remains to be elucidated. We recently reported microarray results demonstrating that increased high-mobility group (HMG) A1a protein expression correlates with increased KL transcription in MCF-7 human breast cancer cells.

The murine testicular transcriptome: characterizing gene expression in the testis during the progression of spermatogenesis.

One of the most promising applications of microarrays is the study of changes in gene expression associated with the growth and development of mammalian tissues. The testis provides an excellent model to determine the ability of microarrays to effectively characterize the changes in gene expression as an organ develops from birth to adulthood. To this end, a developmental testis gene expression time course profiling the expression patterns of approximately 36 000 transcripts on the Affymetrix MGU74v2 GeneChip platform at 11 distinct time points was created to gain a greater understanding of the molecular changes necessary for and elicited by the development of the testis.