Abstract
Tumor necrosis factor receptor p75 (TNF-R p75) is a 75-kDa type I transmembrane protein expressed predominantly on cells of hematopoietic lineage. TNF-R p75 belongs to the TNF receptor superfamily characterized by cysteine-rich extracellular regions composed of three to six disulfide-linked domains. In the present report we have characterized, for the first time, the complete gene structure for human TNF-R p75, which spans approximately 43 kbp. The gene consists of 10 exons (ranging from 34 base pairs to 2.5 kilobase pairs) and nine introns (343 base pairs to 19 kilobase pairs). Consensus elements for transcription factors involved in T cell development and activation were noted in the 5'-flanking region including T cell factor-1, Ikaros, AP-1, CK-2, interleukin-6 receptor E (IL-6RE), ISRE, GAS, NF-kappaB, and Sp1. The unusual (GATA)n and (GAA)(GGA) repeats found within intron 1 may prove useful for further genome analysis within the 1p36 chromosomal locus. Characterization of the human TNF-R p75 gene structure will permit further assessment of its involvement in normal hematopoietic cell development and function, autoimmune disease, and nonrandom translocations in hematopoietic malignancies.
Highlights
Tumor necrosis factor-␣ (TNF-␣)1 and its functionally and structurally related partner, lymphotoxin-␣ (LT-␣) are immunoregulatory cytokines produced primarily by monocytes/ macrophages and activated T lymphocytes in response to bacterial, viral, and parasitic infections
The TNF-R superfamily is characterized by cysteine-rich extracellular regions composed of three to six disulfide-linked domains thought to be important for ligand binding
We report here the complete gene structure for human TNF-R p75
Summary
Tumor necrosis factor-␣ (TNF-␣) and its functionally and structurally related partner, lymphotoxin-␣ (LT-␣) are immunoregulatory cytokines produced primarily by monocytes/ macrophages and activated T lymphocytes in response to bacterial, viral, and parasitic infections. TNF-␣ mediates its diverse biologic effects through two distinct receptors known as TNF-receptor (TNF-R) p55/60 (CD120a) and p75/80 (CD120b), corresponding to their apparent molecular mass of 55/60 kDa and 75/80 kDa, respectively (reviewed in Ref. 2). All receptors in the superfamily bind to a family of ligands with pro-TNF (membrane-bound form) representing the prototypic ligand (reviewed in Ref. 3). While both receptors have been shown to mediate cytotoxicity [4], they have distinct, nonoverlapping functions as well. TNF-R p55 signals for fibroblast growth, endothelial cell activation/adhesion, and anti-viral activity [5, 6], while TNF-R p75 signals for proliferation of thymocytes [7] and peripheral T cells [8], T cell secretion of granulocyte-macrophage colony-stimulating factor [9], inhibition of early hematopoiesis [10], and the inactivation and clearance of TNF by the kidney [11]
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