Cell size regulation by the human TSC tumor suppressor proteins depends on PI3K and FKBP38

• Published in: Oncogene Vol. 22; no. 31; pp. 4786 - 4798
• Main Authors: ROSNER, Margit, HOFER, Katja, KUBISTA, Marion, HENGSTSCHLÄGER, Markus
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 31.07.2003; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Amino Acid Substitution; Animals; Biological and medical sciences; c-Myc protein; Cell cycle; Cell Cycle - physiology; Cell Division - physiology; Cell growth; Cell proliferation; Cell size; Cell Size - physiology; Chromones - pharmacology; Chromosomes; Classical genetics, quantitative genetics, hybrids; Consortia; Cyclin-dependent kinases; DNA microarrays; DNA, Complementary - genetics; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes; Genes, Dominant; Genetic screening; Genetics of eukaryotes. Biological and molecular evolution; HeLa Cells - cytology; Human; Humans; Insects; Kinases; Mammals; Morpholines - pharmacology; Mutants; Mutation; Mutation, Missense; Myc protein; Oligodeoxyribonucleotides, Antisense - pharmacology; Oligonucleotide Array Sequence Analysis; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - physiology; Protein-Serine-Threonine Kinases; Proteins; Proteins - genetics; Proteins - physiology; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc - physiology; Rats; Recombinant Fusion Proteins - physiology; Repressor Proteins - genetics; Repressor Proteins - physiology; Tacrolimus; Tacrolimus Binding Proteins - physiology; Tacrolimus-binding protein; Transfection; TSC1 gene; TSC2 gene; Tuberous sclerosis; Tuberous Sclerosis Complex 2; Tumor suppressor genes; Tumor Suppressor Proteins; Tumors; Human; cell cycle; hamartin; Tumor; TSC2; TSC1; tuberous sclerosis; cell size; tuberin; Protein
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206776

TSC1 and TSC2 are responsible for the tumor suppressor gene syndrome tuberous sclerosis (TSC). Mammalian TSC genes have been shown to be involved in cell cycle regulation. Recently, in Drosophila, these data have been confirmed and TSC genes have further been demonstrated to affect cell size control. Here we provide supporting data for the fact that the latter function is conserved in mammals. Human TSC1 and TSC2 trigger mammalian cell size reduction and a dominant-negative TSC2 mutant induces increased size. These effects occur in all cell cycle phases, are dependent on the activity of the phosphoinositide-3-kinase and are abolished by co-overexpression of a dominant-negative Akt mutant. Two independent naturally occurring and disease-causing mutations within the TSC2 gene eliminate tuberin's capacity to affect cell size control, emphasizing the relevance of this function for the development of the disease. The same mutations have earlier been shown not to affect tuberin's antiproliferative capacity. That the consequences of modulated TSC gene expression on cell proliferation and on cell size can be assigned to separable functions is further supported by two findings: A mutation within the TSC1 gene, earlier shown to still harbor anti-proliferative effects, was found to eliminate the cell size regulating functions. An important mammalian cell size regulator, c-Myc, was found to inhibit tuberin's antiproliferative capacity, but to have no effects on tuberin-dependent cell size control. To obtain further mechanistical insights, microarray screens for genes involved in TSC1- or TSC2-mediated cell size effects were performed. Antisense experiments revealed that the so observed regulation of the FK506-binding protein, FKBP38, plays a role in TSC gene-dependent cell size regulation. These data provide new insights into mammalian cell size regulation and allow a better understanding of the function of human TSC genes.