Evidence for Separable Functions of Tuberous Sclerosis Gene Products in Mammalian Cell Cycle Regulation

• Published in: Journal of neuropathology and experimental neurology Vol. 61; no. 2; pp. 154 - 163
• Main Authors: MILOLOZA, ANGELINA, KUBISTA, MARION, ROSNER, MARGIT, HENGSTSCHLÄGER, MARKUS
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Association of Neuropathologists, Inc 01.02.2002; Lippincott Williams & Wilkins; Oxford University Press
• Subjects: Animals; Biological and medical sciences; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Division - physiology; Cell Line; Cyclin-Dependent Kinase Inhibitor p27; Enzyme Inhibitors - metabolism; Fibroblasts - physiology; Flow Cytometry; Genes, Tumor Suppressor; Humans; Medical sciences; Neurology; Proteins - genetics; Proteins - metabolism; Rats; Repressor Proteins - genetics; Repressor Proteins - metabolism; Transfection; Tuberous Sclerosis - genetics; Tuberous Sclerosis - physiopathology; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors of the nervous system. Phacomatoses; Immunohistochemistry; Cell culture; Flow cytometry; Nervous system diseases; Rat; Pathogenesis; Rodentia; In vitro; Genetic disease; Pathology; Vertebrata; Regulation(control); Mammalia; Tuberin; Animal; Cell cycle; Tumor; Bourneville syndrome
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1093/jnen/61.2.154

Tuberous sclerosis is an autosomal dominant disease affecting approximately 1 in 6,000 individuals. It is caused by mutations in either TSC1 on chromosome 9q34, which encodes hamartin, or TSC2 on chromosome 16p13.3, which encodes tuberin. The growths, named hamartomas, characteristically occur in different organs of patients and are speculated to result from defects in proliferation control. The observation that hamartin and tuberin can interact in vivo suggests that they might function in the same complex. Here we show that hamartin can affect proliferation control independent of the presence of functional tuberin and that binding to hamartin is not essential for tuberin to affect proliferation. Ectopic expression of hamartin negatively regulates proliferation to a similar extent in tuberin-positive and tuberin-negative cells; this is accompanied by binding to tuberin and upregulation of endogenous p27 in tuberin-positive cells and is without effects on p27 expression in the latter. Our data show for the first time that TSC proteins possess separable functions. We further demonstrate that hamartin can deregulate proliferation control by different mechanisms depending on the presence of tuberin. Besides an overlap in many features of patients with TSC1 and TSC2 mutations, data has accumulated that provides evidence for specific clinical differences. This study provides new insights into the cellular roles of TSC proteins and initiates a discussion of whether separable functions of these proteins might be associated with the clinical differences of TSC1- and TSC2-associated disease.