Tuberous Sclerosis Gene 2 Product Modulates Transcription Mediated by Steroid Hormone Receptor Family Members

Abstract

Tuberous sclerosis (TSC) is a genetic disorder that results in the development of hamartomatous lesions in a variety of organ systems. Both the prevalence of the disease and the often devastating consequences of these tumors pose a serious health and medical care problem. The disease has been mapped to two distinct genetic loci in humans, and although the genes (TSC1 and TSC2) for both loci have recently been cloned, their function remains an enigma. Data presented here demonstrates that TSC2 protein can bind and selectively modulate transcription mediated by members of the steroid receptor superfamily of genes. These data place TSC2 into a growing list of nuclear receptor coregulators and strengthen the expanding body of evidence that these coregulators may play critical roles in cellular differentiation. Tuberous sclerosis (TSC)1 is an autosomal dominant neurocutaneous disorder associated with the development of hamartomatous lesions in a wide variety of tissues, including skin, kidney, brain, eye, lungs, and heart (1). The birth frequency has been estimated at approximately 1 in 6000 (2). Pathologically, TSC is classified as a disorder of cellular migration, proliferation, and differentiation. The tumors associated with TSC are diagnostically distinct, very seldom progress to malignancy, but often have very devastating consequences. The most classical are those that occur in the brain, where they frequently cause epilepsy, mental retardation, autism, and/or attention deficit disorders (1, 3). The relatively high prevalence and serious consequences of TSC make it an important health concern both here in the United States and throughout the world.TSC has been genetically linked to two loci in humans (4). About 60% of TSC cases are sporadic, but in families it has autodominant inheritance with high penetrance. TSC was first linked to chromosome 9q34 in 1987 (5), and this locus was termed TSC1. Later studies identified a second locus on chromosome 16p13 (6) that was called TSC2. The focal nature of TSC tumors suggests that TSC1 and TSC2 may function as tumor suppressor genes, and this is further supported by evidence for inactivating TSC2 germ line mutations and loss of heterozygosity at the TSC2 locus in TSC-associated tumors.The genes for both TSC1 and TSC2 have recently been cloned. Both were cloned by consortiums of investigators sequencing the specific regions of chromosome 9 (7) and chromosome 16 (8) to which TSC1 and TSC2 had been mapped, respectively. TSC1, or hemartin as it was named by the authors, encodes a cDNA of 8599 base pairs containing a 1164-amino acid open reading frame. TSC2, or tuberin, also encodes a rather large protein of 198 kilodaltons as specified by a cDNA of 5474 base pairs containing a 1784-amino acid open reading frame. The lack of any obvious structural similarities between TSC1 and TSC2 would suggest their relationship to tuberous sclerosis is either through some functional homology or through some converging function.Very little is known about the function of TSC1. The large TSC2...

Expression profile of tuberin and some potential tumorigenic factors in 60 patients with uterine leiomyomata

“…Tuberin contains a domain that interacts with steroid receptor families, especially with glucocorticoid receptor, to form a complex. 32 This complex is a negative regulator of the transcriptional activity of glucocorticoid receptor. Expression of glucocorticoid receptor in uterus is basically unknown until a recent study from rat uterus showed moderate expression of glucocorticoid receptor in normal endometrium and smooth muscle of the myometrium.…”

Mutation of the 9q34 gene TSC1 in sporadic bladder cancer

“…It is known that it binds to the TSC2 gene product, probably through coiled-coil domains and that it localizes to as yet uncharacterized structures within the cytoplasm (van Slegtenhorst et al, 1998). The TSC2 gene product has been reported to have a GTPase activating protein (GAP) domain and transcription activation domains and has been shown to be a modulator of RXR mediated transcription (Henry et al, 1998) suggesting a role in the regulation of cellular di erentiation. Two other observations that have previously been made suggest possible areas where the TSC1 gene product may function.…”

Altered Cellular Distribution of Tuberin and Glucocorticoid Receptor in Sporadic Fundic Gland Polyps

“…Tuberin and hamartin are multifunctional proteins associated with cell adhesion (31), cell cycle/ proliferation (27,28), and transcriptional signaling (30). Hamartin and tuberin may function in different cellular locations.…”

“…This complex is a strong negative regulator of the transcriptional activity of GCR (30). GCR is known to be an important factor influencing gastric mucosal function and morphology (32,48).…”