Brain tumor formation in tuberous sclerosis depends on erk activation

Abstract

Tuberous sclerosis (TS) is an autosomal dominant disease associated with the formation of usually benign tumors or hamartomas. The disease is connected with upregulation of mammalian target of rapamycin, central regulator of protein translation, which is usually regarded to be activated by Akt kinase. Here, we show for the first time that in all four brain lesions and one angiomyolipoma from TS patients both extracellular signal-regulated kinase (Erk) and p90 ribosomal S6 kinase 1 activation as well as Erk-dependent phosphorylation of p70 ribosomal S6 kinase 1 are markedly elevated whereas Akt, participating in the classical pathway of mammalian target of rapamycin activation is not always activated. Erk activation is also present in TS-derived cell lines. Importantly, Erk inhibition leads to the decrease of proliferation potential of such lines. These results show that Erk is specifically implicated in the pathogenesis of hamartomas.

Evidence of ambiguous differentiation and mtor pathway dysregulation in subependymal giant cell astrocytoma

“…our results are in agreement with Ess and colleagues who found GFaP positive staining in 50% (4/8) of the SEGas they analyzed (15). The results of their work illustrated the inconsistent presence of both glial and neuronal developmental markers in all their tumors and suggested SEGas may develop from postnatally active neuroglial progenitor cells activation is present in all SEGas and may also play a crucial role in tumor formation in tuberous sclerosis patients (19). our data support the observations of other groups, which have shown that LoH is uniquely sporadic in SEGas when compared to other tumors in TSC patients (3)(4)(5).…”

“…one possible explanation for presence of weakly positive immunostaining includes inactivation of the TSC heterodimer by tuberin phosphorylation by akt (18) or Erk (19) in cases without TSC gene mutations. Both akt and Erk kinases are located upstream of the TSC complex and are known to phosphorylate tuberin (TSC-2), which is thought to inhibit the GTPase enhancing activity resulting in mTor activation (Figure 4).…”

Erk activation as a possible mechanism of transformation of subependymal nodule into subependymal giant cell astrocytoma

“…In our earlier study [6] we observed both Akt and Erk hyperactivation in SEGA specimens. We also found that the Erk pathway plays a more important role in tumor formation in TS than Akt, as Erk hyperactivation without Akt was sufficient for tumor progression.…”

“…First of all, we focused on mTOR kinase and its activators. It is already known that both Akt and Erk pathways can be upregulated in SEGAs [6,7]. However, we do not know any previous study on mTOR, Akt or Erk pathways on SEN specimens.…”

“…The effect of Erk on mTOR and, generally, its role in TS pathogenesis are still going through the stage of exploration. In general, the studies are performed on a few samples of SEGAs [5,6]. According to our knowledge, there are no previous investigations on SEN samples involving Akt, Erk or mTOR pathways.…”