Tuberous sclerosis causing mutants of the TSC2 gene product affect proliferation and p27 expression

Abstract

The autosomal dominant disease tuberous sclerosis (TSC) is caused by mutations in either TSC1 on chromosome 9q34, encoding hamartin, or TSC2 on chromosome 16p13.3, encoding tuberin. TSC is characterized by hamartomas that occur in many organs of a ected patients and these have been considered to likely result from defects in proliferation control. Although the true biochemical functions of the two TSC proteins have not been clari®ed, a series of independent investigations demonstrated that modulated hamartin or tuberin expression cause deregulation of proliferation/cell cycle in human, rodent and Drosophila cells. In support of tuberin acting as a tumor suppressor, ectopic overexpression of TSC2 has been shown to decrease proliferation rates of mammalian cells. Furthermore, overexpression of TSC2 has been demonstrated to trigger upregulation of the cyclin-dependent kinase inhibitor p27. We report that three di erent naturally occurring and TSC causing mutations within the TSC2 gene elliminate neither the anti-proliferative capacity of tuberin nor tuberin's e ects on p27 expression. For the ®rst time these data provide strong evidence that deregulation of proliferation and/or upregulation of p27 are not likely to be the primary/only mechanisms of hamartoma development in TSC. These results demand reassessment of previous hypotheses of the pathogenesis of TSC. Oncogene (2001) 20, 4904 ± 4909.

mTORC1 signaling and regulation of pancreatic β-cell mass

“…Chronic administration of rapamycin has been associated with higher incidence of diabetes, although the relative contribution of β-cell dysfunction and insulin resistance to this effect is difficult to dissect. 63,64 It is possible that the alterations in insulin sensitivity could result from the signals from growth factors and nutrients, 69,[100][101][102][103][104][105] induces controlled growth and is rarely associated with malignancy. 106,107 The current evidence supports the concept that mTORC1 is active in states of increased insulin demand and plays a major role in β-cell expansion and proliferation induced by AKT and insulin resistance.…”

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

“…The pathogenic relationship of these two proteins needs further study. p27 has been reported to be functionally associated with tuberin (28,29). The absence of the latter in vitro results in p27 instability and cytoplasmic accumulation.…”

“…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.…”

“…Regulation of hamartin and tuberin remains unknown. It has been reported that tuberin interacts and colocalizes with CDK1, cyclin B1 (27), p27 (28,29), and glucocorticoid receptor (GCR; 30). Hamartin regulates cell-cell adhesion mediated by the ezrin-radixin-moesin (ERM) proteins and the GTPase Rho (31).…”

Tuberin Binds p27 and Negatively Regulates Its Interaction with the SCF Component Skp2

“…The molecular mechanism of tuberin's effects on p27 localization still remains elusive and is currently under investigation in our laboratory. Recently, we found that specific natural occurring disease-causing mutants can still regulate p27 protein stability and proliferation (30). In addition to cell cycle control, p27 has been implicated in the regulation of a wide variety of different cellular processes such as apoptosis, cell growth, or tumorigenesis (25,29,31).…”