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Introduction: Subependymal nodule (SEN) and subependymal giant cell astrocytoma (SEGA) are brain lesions frequently found in tuberous sclerosis (TS). As about 10-15% of SENs enlarge and transform into SEGAs, we examined here the possible mechanism of the phenomenon., Material and Methods: Using Western blot we studied 1 SEN and 3 SEGA samples; SEN and 1 SEGA came from the same TS patient. We evaluated e.g. the activation of the phosphorylated forms of proteins belonging to Akt, Erk and mTOR pathways., Results: Differences in Erk pathway activation between SEN and SEGA were found. There was no upregulation of p-Erk, p-Mek or p-RSK1 in the SEN specimen, whilst we found these proteins to be significantly uptriggered in SEGA samples. Also, for the first time, we found p-Akt, p-GSK3 and p-PDK1 upregulated in both SEN and SEGA from the same TS patient., Conclusions: Our current study shows for the first time the possible mechanism of SEN/SEGA transformation, where Erk pathway hyperactivation seems to be significant. We hypothesize that SEN/SEGA transformation may depend on Erk potentiation.

Ganglioglioma (GG) is a low-grade neoplasm, often associated with intractable epilepsy in pediatric patients. Available data suggest a relationship between GG and other glioneuronal lesions. So far, little is known about activation of kinases belonging to the mTor (mammalian target of rapamycin) pathway, although its upregulation is often found in brain tumors. Involvement of mTor kinase is responsible for excessive proliferation. In the current study we focused on the possible role of the Erk/Mapk (extracellular-signal-regulated kinase/mitogen-activated protein kinase) pathway in GG development. Eight GG tumors were resected from pediatric patients. Collected data reveal activation of proteins from the Erk pathway: Mek (extracellular regulated protein kinase kinase/mitogen-activated protein kinase kinase), Erk, Rsk1 (ribosomal S6 kinase 1), Rheb (Ras homolog enriched in brain) and Msk1 (mitogen- and stress-activated protein kinase 1), as detected by the western blot method. Moreover, activation of other proteins upstream of mTor - IGF-1R β (insulin-like growth factor 1β receptor), INR β (insulin receptor β), Akt/PKB (protein kinase B) - or downstream - 4E-BP1 (eukaryotic translation initiation factor 4E-binding protein 1) and rpS6 (ribosomal protein S6) - was also confirmed.

Medulloblastoma with extensive nodularity (MBEN) is the only type of medulloblastoma (MB), an aggressive CNS tumour of childhood, that is connected with favourable prognosis. In patients with MBEN tumour resection and chemotherapy are sometimes sufficient. While development of other types of MB is usually connected with activation of the wingless pathway, sonic hedgehog pathway or mammalian target of rapamycin (mTor) pathway, little is known about the molecular basis of MBEN pathophysiology. In the present paper we evaluated activation of the mTor pathway and kinases upstream of mTor, mitogen-activated protein kinase (MAPK/Erk) and protein kinase B (PKB/Akt) in an MBEN sample. Using western blot technique with antibodies directed against active, phosphorylated forms of proteins, we found upregulation of mTor, Akt and Erk. Thus we postulate that the mTor pathway, often implicated in the development of CNS tumours, is also responsible for MBEN progression. Especially interesting seems implication of Erk and other kinases belonging to the same pathway: mitogen-activated protein kinase kinase (MEK-1) or phospho-ribosomal S6 kinase-1 (p90 RSK1), whose activity we usually demonstrate in more benign neoplasms. However, it remains to be clarified whether Erk pathway activation is actually prognostic for benign tumour development.

A typical teratoid/rhabdoid tumor (AT/RT) is a highly malignant childhood brain tumor. Most AT/RTs are shown to contain chromosome 22 mutation in the region of hSNF5/INI1 gene, whose protein product participates in chromatin remodeling. Although the presence of this mutation is well described, molecular pathways underlying AT/RT development are poorly, if at all, understood. In the current paper we evaluate a case of AT/RT with special consideration of two pathways often implicated in tumor development: protein kinase B (PKB or Akt) and extracellular signal-regulated kinase (Erk). First, we confirmed expression of typical protein pattern being unique for AT/RT, including epithelial membrane antigen, S-100 and glial fibrillary acidic protein. In molecular analyses we tested the sample for activity of Akt and Erk kinase cascade. We found that Erk pathway signaling in the tumor was not upregulated. Neither c-Raf, MAPK nor Erk were hyperphosphorylated. On the other hand, we detected significant phosphorylation of Akt, phosphoinositide-dependent kinase-1 (PDK1) and glycogen synthase kinase 3 (GSK-3). At the same time, inhibitor of Akt pathway, phosphatase and tensin homolog (PTEN), was not upregulated. These results strongly support the hypothesis that Akt pathway contributes to chromatin remodeling disruption, promoting malignant transformation of AT/RT.

The long-term outcome of peripheral nerve injury is often unsatisfactory, especially if the injury resulted in a gap between transected nerve stumps. Brain-derived neurotrophic factor and its receptor, trkB, are strongly implicated in the early phase of axonal regeneration after injury. We examined the role of trkB in long-term functional and morphological outcome of peripheral nerve injury. The sciatic nerve was transected in wild-type and heterozygous trkB-deficient mice. The nerve was either left cut or immediately sewn up or the gap injury model was performed. The gap was provided with autologous or cross (obtained from other genetic group) graft. Sciatic nerve function as well as autotomy was assessed during 16-week follow-up. The long-term functional outcome of nerve cut or immediately rejoined did not differ between wild-type and trkB-deficient mice. Gap injury provided with nerve graft resulted in better functional outcome in trkB-deficient mice than wild-type animals. Sixteen weeks after the surgery, the animals were sacrificed and histological evaluations were performed. The number of nerve fibres regenerating into the distal stump of transected and rejoined nerves did not differ between wild-type and trkB-deficient animals. TrkB deficiency markedly increased the number of Schwann cells as well as mast cells at the injury site and in the distal stump of the regenerating nerve. TrkB deficient nerves also showed higher expression of bcl-2 protein but lower of trkA and NGF than wild-type ones. Our results show for the first time the possible deleterious role of trkB receptor in long-term outcome of peripheral nerve injury.

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).