TSC1 is a tumor suppressor gene that encodes a 130 kDa protein called hamartin. TSC1 was first identified as an oncogenic driver of Tuberous Sclerosis, a condition characterized by numerous benign tumors of the skin, brain, heart, and lungs. A mutation in TSC1 is responsible for the uncontrolled growth characteristic of these tumors. This discovery led to a greater understanding of the physiologic role of TSC1 as a negative cell cycle regulator. The distinct but related gene TSC2 encodes a 200 kDa protein called tuberin. TSC1 and TSC2 heterodimerize to form a complex that acts as a GTPase-activating protein (GAP) for the G-protein Rheb (1). Rheb is a member of the Ras family that inhibits mTORC1 signaling when activated by the TSC1-TSC2 complex. mTORC1 signaling promotes cell growth and proliferation and aberrant signaling promotes tumor formation. The TSC1-TSC2 complex acts as a sensor for levels of growth factors, amino acids, and other essential nutrients. Phosphorylation of the TSC1-TSC2 complex by Akt and ERK inhibit its GAP activity (2). In contrast, phosphorylation by AMPK stabilizes the complex to promote GAP activity and inhibition of mTORC1 signaling.
Miloloza et. al. used the TSC1 antibody to compare TSC1 expression levels throughout the different phases of the cell cycle (3). The group found that TSC1 (hamartin) was present in roughly equal amounts throughout the cell cycle, regardless of the expression of TSC2 (tuberin). This led the group to further investigate the interaction between TSC1 and TSC2 using the TSC1 antibody for co-immunoprecipitation experiments. The TSC1-TSC2 complex was identified in every phase of the cell cycle. To clarify the role of TSC1 in cell cycle regulation, the group transfected HeLa cells with full length TSC1. They confirmed TSC1 expression using the TSC1 antibody for immunoblot and compared the growth curve of the TSC1-transfected cells to their control. The TSC1 transfected cells had a highly attenuated growth rate compared to the controls, supporting the role of TSC1 as a negative cell cycle regulator.
Bartolomé et. al. used the TSC1 antibody to elucidate a role for the TSC1-TSC2 complex in differential pancreatic β-cell signaling (2). The group used the TSC1 antibody to confirm TSC1 expression levels in all of their cell lines and knockdowns. Through specific knockdowns, the group identified the TSC1-TSC2 complex as an integration point for insulin and glucose signaling. They reported that insulin exerted its effects through PI3K/Akt and MEK/ERK phosphorylation of the TSC1-TSC2 complex. Meanwhile, glucose exerted its effects through MEK/ERK and AMPK phosphorylation.
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