Maciej Lazarczyk

Positive and negative regulation of TSC2 activity and its effects on downstream effectors of the mTOR pathway

Tuberous sclerosis is an autosomal-dominant disorder caused by the mutation of one of the two tumor suppressor genes: TSC1 or TSC2, encoding protein products, hamartin, and tuberin, respectively. Both proteins form intracellular complexes exerting inhibitory activity on mammalian target of rapamycin (mTOR) kinase. It has been demonstrated that signal transduction from tuberin to mTOR is mediated by a G protein, Ras homologue enriched in brain (Rheb). In normal cells, tuberin having GTPase-activating protein properties toward Rheb controls signals of nutrient depletion, hypoxia, or stress, not allowing activation of mTOR and subsequent protein translation and cell proliferation. However, when environmental conditions change, tuberin is phosphorylated and it forms a complex with hamartin is degraded, and downstream targets of mTOR, S6K, and eEF2K, can be activated. In this review, we summarize very recent information contributing to our knowledge of TSC2 regulation by four cellular signaling pathways: PI3K/Akt, Ras/MAPK, LKB1/AMPK, and REDD1.

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.

Immunostimulatory oligonucleotides in therapy of allergic diseases

At present, the improvement of hygienic life standards is considered as an environmental condition, increasing the prevalence of allergic diseases, as early contact with some pathogens is, according to the hygiene hypothesis, required for maturation of the immune system. The recognition of microbial components involves acquired and innate immunity mechanisms. Recently, the link between innate and acquired immunity has been discovered. It involves the evolutionarily old Toll-like receptor (TLR) system. Ligands recognised by TLRs include unmethylated deoxycytidil-deoxyguanosine (CpG) motif-containing microbial DNA. TLR-mediated signalling induces expression of cytokines preferentially promoting a Th1-directed response. Therefore, synthetic CpG motif-containing immunostimulatory oligonucleotides could be employed in causal allergy treatment. This review discusses some molecular aspects of the TLR system, as well as results of animal studies and early experiences, including treatment safety, from human clinical trials with immunostimulatory CpG motif-containing oligonucleotides.