Mutations in the TSC1 or TSC2 genes cause tuberous sclerosis, a benign tumour syndrome in humans. Tsc2 possesses a domain that shares homology with the GTPase-activating protein (GAP) domain of Rap1-GAP, suggesting that a GTPase might be the physiological target of Tsc2. Here we show that the small GTPase Rheb (Ras homologue enriched in brain) is a direct target of Tsc2 GAP activity both in vivo and in vitro. Point mutations in the GAP domain of Tsc2 disrupted its ability to regulate Rheb without affecting the ability of Tsc2 to form a complex with Tsc1. Our studies identify Rheb as a molecular target of the TSC tumour suppressors.

New technologies for the detection and therapy of early stage breast cancer are urgently needed. Pathological changes in breast might be reflected in proteomic patterns in serum. A proteomic tool was used to identify proteomic patterns in serum that distinguishes neoplastic from non-neoplastic disease within the breast. Preliminary results derived from the serum analysis from 54 unaffected women and 76 patients with breast cancer were analyzed by two-dimensional (2-D) electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry, HSP27 was found up-regulated while 14-3-3 sigma was down-regulated in the serum of breast cancer patients. The two protein biomarkers were then used to classify an independent set of 104 masked serum samples. The results showed that the protein pattern on 2-D gels can completely segregate the serum of breast cancer from non-cancer. The discriminatory pattern correctly identified all 69 breast cancer cases in the masked set. Of the 35 cases of non-malignant disease, 34 were recognized as non-cancer. These findings justify a prospective population-based assessment of proteomic technology as a screening or diagnostic tool for breast cancer in high-risk and general populations. These two protein biomarkers could also be used as targets for further study in drug design and breast cancer therapy.

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