Upregulation of the WNT pathway in tuberous sclerosis-associated subependymal giant cell astrocytomas.

Tuberous sclerosis (TS), autosomal dominant disorder manifested by the formation of usually benign tumors in the brain, heart, kidneys and skin, results from an inactivating mutation in one of two tumor suppressor genes TSC1 or TSC2. Protein products of these genes, hamartin and tuberin, respectively, have been shown to participate in the mTOR pathway controlling translation of approx. 10-15% of all proteins. In the current paper, we aimed at verifying whether hamartin and tuberin may also be implicated in the control of gene transcription. Very recently it has been hypothesized that the pathway triggered by WNT, one of embryonic growth factors involved in cell differentiation and migration, could be disturbed in TS. In order to test this hypothesis we evaluated samples of four subependymal giant cell astrocytomas (SEGAs), brain tumors developing in the progress of TS. We found that beta-catenin, transcription factor and mediator of WNT pathway activity is indeed present and active in SEGAs. mRNA transcripts for c-Myc and N-Myc, proteins whose transcription is regulated by beta-catenin, were upregulated in two of four SEGAs, while cyclin D1 mRNA was significantly higher in three SEGAs. At the same time, c-Myc and N-Myc proteins were detected in the same two samples. Thus, we show for the first time that aberrant WNT signaling may contribute to the pathogenesis of TS-associated SEGAs.

Activation of Akt and Erk pathways in medulloblastoma.

Medulloblastoma (MB) is the most common malignant brain tumour in children. Its aetiology is unknown, although several signalling pathways controlling cell proliferation are thought to participate in the progress of the neoplasm. Mutations of the genes encoding proteins participating in the pathways triggered by embryonic growth factors like Sonic hedgehog (Shh) or WNT are often found in MB. Another model of MB development is overexpression or mutation of several types of growth factor receptors, including IGF-IR, EGF-R and PDGFR, that have the ability to activate cellular kinases responsible for promoting cell proliferation. In order to test this hypothesis, in the current paper we tested the activation of two kinases, Akt/PKB (protein kinase B) and Erk (extracellular signal-regulated kinase) and their substrates in 10 sporadic medulloblastoma cases. We show that MBs are a highly heterogeneous group of tumours that show upregulation of various signalling pathways. Nevertheless, both Akt and Erk may contribute to the progression of MB, triggering, at least in some cases, the mTOR (mammalian target of rapamycin) pathway, controlling translation of several cell cycle-related proteins. We hypothesize that Akt and Erk activation may also be associated with downregulation of protein phosphatase 2A (PP2A).