The Drosophila Tuberous Sclerosis Complex Gene Homologs Restrict Cell Growth and Cell Proliferation

Abstract

The inherited human disease tuberous sclerosis, characterized by hamartomatous tumors, results from mutations in either TSC1 or TSC2. We have characterized mutations in the Drosophila Tsc1 and Tsc2/gigas genes. Inactivating mutations in either gene cause an identical phenotype characterized by enhanced growth and increased cell size with no change in ploidy. Overall, mutant cells spend less time in G1. Coexpression of both Tsc1 and Tsc2 restricts tissue growth and reduces cell size and cell proliferation. This phenotype is modulated by manipulations in cyclin levels. In postmitotic mutant cells, levels of Cyclin E and Cyclin A are elevated. This correlates with a tendency for these cells to reenter the cell cycle inappropriately as is observed in the human lesions.

JNK pathway mediates apoptotic cell death induced by tumor suppressor LKB1 in Drosophila

“…17,18 Since reduction in cell size is a typical outcome of TSC overexpression, we attempted to test whether the LKB1 overexpression phenotype results from cell size reduction. 39,40 As expected, the overexpression clones of TSC (Figure 2i) displayed a dramatic reduction in wing marginal bristle size. However, surprisingly, although LKB1 reduced clone size more severely than did TSC, LKB1 expression did not cause any alterations in the bristle size (Figure 2g, h).…”

“…39,42,56 This study presented that tumor suppressor LKB1 also negatively regulates organ size in Drosophila in a kinase activity-dependent manner (Figure 1). Recent reports on the TSC tumor suppressor suggested that LKB1 suppresses TOR activity via the TSC complex, ultimately resulting in inhibition of cell growth and proliferation.…”

“…Similarly, overexpression of the TSC complex, another well-known tumor suppressor, also decreased the clone size, although with a milder severity than the overexpression of LKB1 (Figure 2c, f). 39 Recent mammalian studies suggested that LKB1 negatively regulates TOR signaling via the AMPK-TSC pathway. 17,18 Since reduction in cell size is a typical outcome of TSC overexpression, we attempted to test whether the LKB1 overexpression phenotype results from cell size reduction.…”

Mutational Analysis of the von Hippel Lindau Gene in Clear Cell Renal Carcinomas from Tuberous Sclerosis Complex Patients

“…Pathways in which tuberin, the TSC2 gene product, is believed to participate include vesicular trafficking (42) and cell cycle regulation (43,44). Hamartin, the TSC1 gene product, also regulates the cell cycle (45)(46)(47)(48) and affects focal adhesion formation via activation of the GTPase Rho (49). To date, no direct connections between the functions of hamartin and tuberin and the function of the VHL protein, pVHL, have been identified.…”

Stress and mTORture signaling

“…Spurred by genetic studies carried out in Drosophila, the TSC1 (tuberous sclerosis complex) (Hamartin)/ TSC2 (Tuberin) tumor suppressor complex was identified as a negative growth regulator upstream of TOR (Gao and Pan, 2001;Potter et al, 2001;Tapon et al, 2001;Kwiatkowski and Manning, 2005). Mutations in either gene causes hypertrophic and hyperplastic phenotypes leading to hamartoma syndromes (Kwiatkowski and Manning, 2005).…”