Publications

The cytokines IL-4, IL-13, and IL-5 are markers for the Th2 subset of effector T cells and are often expressed together. These cytokine genes are organized within 140 kb of orthologous DNA in both mouse and human. Using IL-4-expressing CD4+ T cell clones derived from F1 mice, we identified allelic polymorphisms for each of these cytokines and assessed the parental identity of the cytokine mRNAs. Both monoallelic and biallelic expression occurred for each gene and for an additional gene, IL-3, that lies with GM-CSF over 450 kb telomeric on the same chromosome. When coexpressed in T cell clones, IL-4 was expressed from the same allele as IL-13 or IL-5 in 81% of instances. In contrast, there was only 52% concordance of these three cytokines at the allelic level among clones that expressed IL-3. Independent expression of the cytokine alleles occurs commonly in T cells, but the clustered locus encompassing IL-4, IL-13, and IL-5 is subject to coordinate regulation.

The methylpurine-DNA glycosylase (MPG) gene coding for human 3-methyladenine (3-meAde)-DNA glycosylase functions in the first step of base excision repair (BER) to remove numerous damaged bases including 3-meGua, ethenoadenine, and hypoxanthine (Hx) in addition to 3-meAde. In this report, we identify the length of the minimal MPG promoter region, demonstrate the involvement of several transcription factors in expression of the MPG gene, and determine the point at which transcription initiates. We also demonstrate that control of MPG expression is linked to MPG activity. To initiate studies on how the MPG functions with the ensemble of BER genes to effect repair, we have investigated the cell cycle control of MPG and other BER genes in normal human cells. Steady-state mRNA levels of MPG, human Nth homologue (NTH), and uracil-DNA glycosylase (UDG), DNA glycosylases, and human AP site-specific endonuclease (APE), an endonuclease incising DNA at abasic sites, are cell cycle dependent. In contrast, expression levels of genes coding for human 8-oxoguanine-DNA glycosylase (OGG1) and TDG DNA glycosylases, and omicron 6-methylguanine-DNA methyltransferase (MGMT) gene, and the RPA4 subunit gene do not vary with cell cycle. These observed cell cycle dependent differences might reflect distinct roles of individual BER proteins in mutation avoidance.

Many physiologic roles of PTHrP are emerging. The protein functions locally in diverse tissues, often regulating the entry of cells into a differentiation pathway or acting as an epithelial signal in epithelial-mesenchymal interactions. To carry out these functions, PTHrP uses the receptor it shares with PTH or one of several PTHrP receptors that have evolved to recognize selectively the PTH-like region of PTHrP or other domains. Thus, PTHrP is a polyhormone. An exquisite selectivity barrier allows PTHrP to carry out its local tissue functions at the same time PTH uses their shared receptor to regulate systemic calcium homeostasis. This barrier is breached under pathologic circumstances, such as when malignant tumors secrete enough PTHrP into blood to cause PTH-like effects, including hypercalcemia. Powerful genetic models that have been developed in the past 7 years promise to give continuing insights into the physiology and pathophysiology of PTHrP.

Medical therapy is useful in cases of acute primary hyperparathyroidism, patients with recurrent disease, and parathyroid carcinoma. Among the therapeutic agents that have been employed, oral phosphate, bisphosphonates, and estrogens have been successful. The newly described calcimimetic agents directly block secretion of parathyroid hormone from the glands and offer an important new approach to medical therapy of primary hyperparathyroidism.