Distribution of Tsc1 Protein Detected by Immunohistochemistry in Various Normal Rat Tissues and the Renal Carcinomas of Eker Rat: Detection of Limited Colocalization with Tsc1 and Tsc2 Gene Products In Vivo

Abstract

SUMMARY:We and others previously demonstrated that hereditary mutation and a subsequent second hit in the rat homolog of tuberous sclerosis gene (Tsc2) are responsible for Eker renal carcinomas (RC). In humans, alteration in the TSC2 gene is known to cause the tuberous sclerosis complex (TSC) that results in hamartomatous lesions in multiple organs, but the function of TSC2 is not fully understood. In recent years, a second gene (TSC1) responsible for human TSC has been cloned, and binding between TSC1 and TSC2 proteins was reported. In this study, to clarify associations between Tsc proteins in vivo, the expression of Tsc1 protein was detected by immunohistochemistry, and compared with Tsc2 expression. Tsc1 protein was expressed in the nervous system and in many endocrine tissues, including pancreatic islets, the parathyroids, testis, and ovary. Tsc1 was also detected in the many epithelial tissues of organs, such as kidney, uterus, small and large intestine, and liver. Our results indicate overlapping, but not identical, organ distributions of Tsc1 and Tsc2 proteins. At the intracellular distribution, double fluorescent immunolabeling allowed the determination that only a partial portion of Tsc1 signals overlapped with Tsc2 in some organs. These results suggest the existence of co-localizing and independent forms of Tsc proteins in endogenous expressions. Additionally, relatively high expression of Tsc1 protein was detected in RC in the Tsc2 mutant (Eker) rat. (Lab Invest 2000, 80:1347-1359.

Tuberin Nuclear Localization Can Be Regulated by Phosphorylation of Its Carboxyl Terminus

“…Like tuberin, hamartin has also been reported to localize to the nucleus (40). If hamartin localizes to the nucleus, a reasonable question would be, do these proteins function within the nucleus as a heterodimer or independently?…”

Molecular Pathogenesis of Lymphangioleiomyomatosis

“…This association has been demonstrated by immunohistochemical colocalization studies (58)(59)(60)(61)(62)(63) as well as by coimmunoprecipitation from subcellular fractions (64). In their elegant series of experiments, Nellist and colleagues (44) showed that hamartin and tuberin are binding partners that coelute from subcellular fractions in a complex with a molecular weight of 450 kD, larger than the combined molecular weights of hamartin and tuberin.…”

Tuberin – A New Molecular Target in Alzheimer’s Disease?

“…In rodent organs such as the adrenal, brain, pituitary, small and large intestine, stomach, testis, and retina, the distribution of hamartin and tuberin overlapped, but was not identical, suggesting that hamartin does not always associate with tuberin in all organs and tissues. At the subcellular levels, the two proteins co-localized with each other to some extent, but localization was mostly independent in pancreatic islets, medulla of the kidney, and muscle fibers (24,25). Analysing kidney biology revealed that tuberin and hamartin are specifically expressed in the distal urinary tubule.…”