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

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 affected 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 clarified, 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 different naturally occurring and TSC causing mutations within the TSC2 gene eliminate neither the anti-proliferative capacity of tuberin nor tuberin's effects on p27 expression. For the first 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.