Neurology India
menu-bar5 Open access journal indexed with Index Medicus
  Users online: 5177  
 Home | Login 
About Editorial board Articlesmenu-bullet NSI Publicationsmenu-bullet Search Instructions Online Submission Subscribe Videos Etcetera Contact
  Navigate Here 
 Resource Links
  »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
  »  Article in PDF (1,811 KB)
  »  Citation Manager
  »  Access Statistics
  »  Reader Comments
  »  Email Alert *
  »  Add to My List *
* Registration required (free)  

  In this Article
 »  Abstract
 » Introduction
 »  Materials and Me...
 » Results
 » Discussion
 » Conclusion
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    PDF Downloaded61    
    Comments [Add]    
    Cited by others 1    

Recommend this journal


Table of Contents    
Year : 2016  |  Volume : 64  |  Issue : 5  |  Page : 988-994

Role of mTOR signaling pathway in the pathogenesis of subependymal giant cell astrocytoma – A study of 28 cases

1 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India
3 Institute of Genomics and Integrative Biology–Council of Scientific and Industrial Research, New Delhi, India
4 Department of Pathology, GB Pant Hospital, New Delhi, India

Date of Web Publication12-Sep-2016

Correspondence Address:
Mehar C Sharma
Department of Pathology, All India Institute of Medical Sciences, New Delhi - 110 029
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.190274

Rights and Permissions

 » Abstract 

Background: Subependymal giant cell astrocytomas (SEGA) are slow-growing benign intraventricular tumors, the pathogenesis of which is debated. Recent studies have shown that tuberous sclerosis complex (TSC) 1 and TSC2 genes are linked to the mammalian target of rapamycin (mTOR) cell signaling pathway. We aimed to analyze TSC1 and TSC2 gene mutation, hamartin and tuberin protein expression, and protein expression of mTOR signaling cascade in a series of SEGA to determine their role in pathogenesis.
Materials and Methods: Twenty-eight SEGA cases were retrieved from archival material. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue using antibodies against tuberin, hamartin, phospho-p70S6 kinase, S6 ribosomal protein, phospho-S6 ribosomal protein, phospho-4E-BP1, Stat3, and phospho-Stat3. Mutation analysis of TSC1 (exons 15 and 17) and TSC2 (exons 33, 39, and 40) was done by DNA sequencing.
Results: Loss of immunoexpression of either hamartin or tuberin was found in 19 cases (68%). Pathogenic point mutations in selected exons of TSC1 and TSC2 genes were present in 5 of 20 cases studied. Robust expression of mTOR downstream signaling molecules phospho-p70S6 kinase (100%), S6 ribosomal protein (82%), phospho-S6 ribosomal protein (64%), phospho-4E-BP1 (64%), and Stat3 (100%) was seen. Four cases (14%) showed immunopositivity for phospho-Stat3. There was no significant correlation of these markers with immunoloss of tuberin and hamartin.
Significance: There is a definite role for TSC1 and TSC2 genes in the pathogenesis of SEGA as evidenced by loss of protein expression and presence of mutations. Strong expression of mTOR downstream signaling proteins indicates activation of mTOR pathway in these tumors, suggesting that proteins in this pathway may have the potential to serve as therapeutic targets in these patients.

Keywords: Brain tumors; hamartin; mTOR; Phospho-p70S6 kinase; subependymal giant cell astrocytoma; tuberin; tuberous sclerosis complex

How to cite this article:
Kumari K, Sharma MC, Kakkar A, Malgulwar PB, Pathak P, Suri V, Sarkar C, Chandra SP, Faruq M, Gupta RK, Saran RK. Role of mTOR signaling pathway in the pathogenesis of subependymal giant cell astrocytoma – A study of 28 cases. Neurol India 2016;64:988-94

How to cite this URL:
Kumari K, Sharma MC, Kakkar A, Malgulwar PB, Pathak P, Suri V, Sarkar C, Chandra SP, Faruq M, Gupta RK, Saran RK. Role of mTOR signaling pathway in the pathogenesis of subependymal giant cell astrocytoma – A study of 28 cases. Neurol India [serial online] 2016 [cited 2020 Sep 30];64:988-94. Available from:

 » Introduction Top

Subependymal giant cell astrocytomas (SEGA) are World Health Organisation (WHO) grade I intraventricular tumors occurring in 6–14% of individuals with tuberous sclerosis complex (TSC).[1] TSC is an autosomal dominant disorder resulting from mutations of genes TSC1 and TSC2, diagnosed clinically, based on the standard criteria.[2],[3],[4] Presence of SEGA is a major criterion for the diagnosis of TSC. Detectable as early as 23 weeks after birth, these slow-growing tumors typically present with features of obstructive hydrocephalus in the second decade of life.[5] Occurrence of SEGA outside of TSC is debatable. TSC1 and TSC2 genes function as tumor suppressors, encoding for the proteins hamartin and tuberin. These proteins form the central component of the pathway that modulates insulin-like growth factor-mediated cell signaling, which regulates cell growth and proliferation by inhibiting the mammalian target of rapamycin (mTOR) pathway.[6],[7] Mutations in TSC genes and resultant inactivation of hamartin or tuberin cause excessive phosphorylation of mTOR signaling proteins leading to defective cell migration and cytomegaly, thus resulting in the characteristic lesions of TS, such as tubers, nodules, and hamartomas in multiple organs, including the brain, kidney, skin, and heart.[8],[9] Mutations in TSC1 and TSC2 have also been shown to affect neuronal differentiation, resulting in a stem cell phenotype.[8] Till date, 135 mutations of TSC1 and 360 mutations of TSC2 gene have been reported in TSC, with causative mutations occurring in almost all exons. No mutational hot spots are defined, a significant drawback considering the large size of the genes.[10] The pathogenesis of SEGA in TSC is uncertain. Several studies have attempted to define the phenotype of the different cells types found in SEGA, viz., giant cells, dysmorphic neurons, and astrocytes. However, the results have not been conclusive. With this background, we aimed to look for TSC1 and TSC2 mutations, analyze the immunoexpression of tuberin and hamartin, and elucidate the role of mTOR pathway activation in the pathogenesis of SEGA.

 » Materials and Methods Top

All cases of SEGA resected for treatment of medically intractable epilepsy, diagnosed between 1982 and 2013, were retrieved from the archives of two institutes, All India Institute of Medical Sciences, New Delhi (AIIMS), and G.B. Pant Hospital, New Delhi (GBPH). Hematoxylin-and-eosin–stained slides were reviewed for confirmation of the diagnosis by two neuropathologists (M.C.S., V.S.). Clinical data were also obtained.


Five-micron-thick sections cut from formalin-fixed, paraffin-embedded (FFPE) tissue blocks were immunolabeled with the following antibodies using standard protocol: Hamartin (dil 1:400; Novacastra, UK), tuberin (dil 1:25; Acris, Germany), phospho-p70S6 kinase (Thr389; dil 1:100; Cell Signalling, MA, USA), S6 ribosomal protein (dil 1:50; Cell Signalling, MA, USA), phospho-S6 ribosomal protein (dil 1:400; Cell Signalling, MA, USA), phospho-4E-BP1 (Thr37/46; dil 1:1600, Cell Signalling, MA, USA), Stat3 (dil 1:600; Cell Signalling, MA, USA), and phospho-Stat3 (dil 1:200; Cell Signalling, MA, USA). Sections from normal brain cortex were used as controls. Staining for phospho-p70S6 kinase, S6 ribosomal protein, phospho-S6 ribosomal protein, phospho-4E-BP1, Stat3, and phospho-Stat3 was estimated as follows: No staining, 0; faint positivity in <10% of cells, 1+; moderate positivity in 10–50% of cells, 2+; and, strong positivity in ≥50% of cells, 3+. Only 2+ and 3+ staining were considered as positive.[11]

DNA extraction and sequencing

DNA was extracted from tumor samples with adequate material in the FFPE blocks. Eight serial sections of 10-µ thickness were collected from each block. Recover All™ Total Nucleic Acid Isolation Kit (Ambion, Texas, USA) was used to extract DNA as per the manufacturer's instructions. Exons 15 and 17 of TSC1 gene and exons 33, 39, and 40 of TSC2 gene were selected for mutation analysis, as they are the most frequently mutated warm spots.[12] Polymerase chain reaction (PCR) amplification was carried out using forward and reverse primers [Table 1], in a 10-µl reaction mixture containing 50 ng of DNA, 1 µl of 10× PCR buffer, 0.8 µl of 10 mM dNTPs, 0.25 µl each of forward and reverse primers, and 0.2 µl of AmpliTaq Gold PCR Master mix (Applied Biosystems, California, USA). Initial denaturation was carried out at 95°C for 1 minute, annealing at 57°C for 45 seconds, and extension at 72°C for 2 minutes. Bidirectional sequencing was performed using ABI 3730 sequencer (Applied Biosystems, California, USA). Mutation analysis was done using “Mutation Taster” online software, for predicting disease-causing potential of sequence alterations.
Table 1: TSC gene exons sequenced and primers used

Click here to view

 » Results Top

A total of 28 cases of SEGA were identified [Table 2], 21 from AIIMS and 7 cases from GBPH. The median age of the patients was 15 years (range, 2–60 years), with a male:female ratio of 3:1. Of the 28 patients, 10 met the criteria for clinical diagnosis of TSC, with presence of other associated lesions such as adenoma sebaceum, tubers, angiomyolipoma, and polycystic kidney disease. Tumors were located predominantly in the left lateral ventricle (19 of 28 cases, 68%), whereas 32% (9 of 28 cases) were in the right lateral ventricle. All patients presented with seizures, with the duration of symptoms ranging from as less as 15 days to as long as 7 years (median, 0.8 years). The mean duration of seizures in patients with TSC was considerably longer (1.3 years; range: 0.08 to 7 years) as compared with those without TSC (0.62 years; range, 15 days to 2 years).
Table 2: Clinical details of patients with a subependymal giant cell astrocytoma

Click here to view

Histopathological features

All cases showed a similar histology. Microscopic examination revealed moderate cellularity, composed of three different populations of cells, viz., large pleomorphic ganglion-like cells with abundant glassy eosinophilic cytoplasm, gemistocytic astrocytes, and spindled cells. Areas of dystrophic calcification, lymphocytic and mast cell infiltrates, and presence of hyalinized and thickened blood vessels were frequent, while mitoses, microvascular proliferation, and necrosis were absent [Figure 1]. One case also showed the presence of a tuber in the adjacent brain parenchyma.
Figure 1: Photomicrographs showing SEGA adjacent to ventricular lining epithelium (a; hematoxylin and eosin [HE], ×200). Tumor comprises giant cells with abundant glassy eosinophillic cytoplasm and eccentric vesicular nuclei with conspicuous nucleoli (b; HE, ×400). Spindling of tumor cells (c; HE, ×400) and foci of dystrophic calcification (d; HE, ×400) are seen

Click here to view


Expression of hamartin and tuberin

Loss of hamartin immunoexpression alone was seen in

eight cases (28%), while loss of tuberin alone was seen in nine cases (32%). One tumor (4%) showed loss of both hamartin and tuberin, while 36% (10 of 28) did not show loss of either protein. Loss was observed in the giant cell, spindle cell, and astrocytic components of the tumors. Loss of immunoexpression was irrespective of a clinical diagnosis of TSC (P = 0.99). The single case of SEGA that showed loss of both hamartin and tuberin also showed this dual loss in the cortical tuber (case 11) [Figure 2]a and [Figure 2]b.
Figure 2: Immunohistochemistry showing loss of hamartin (a; ×400) and tuberin (b; ×400) in tumor cells. Robust expression of phospho-p70S6 kinase (c; ×400) and S6 ribosomal protein (d; ×400), and overexpression of phospho-S6 ribosomal protein (e; ×400) and phospho-4E-BP1 (f; ×400), are seen in tumor cells. Stat3 cytoplasmic positivity (g; ×400), focal nuclear positivity for phospho-Stat3 (h; ×400), and tumor cells immunonegative for phospho-Stat3 (I; ×400) are shown

Click here to view

Activation of mTOR cascade

In SEGA, overexpression of p70S6 kinase was seen in all cases (100%). Ribosomal S6 protein was overexpressed in 23 cases (82%), whereas phospho-S6 ribosomal protein was seen in 18 cases (64%). Immunoreactivity for phospho-4E-BP1 was seen in 18 cases (64%). All cases showed strong immunoreactivity for Stat3 (100%), while only four cases (14%) showed strong but focal expression of phospho-Stat3. Normal adult neocortex included as control showed faint immunostaining of neurons for phospho-p70S6 kinase, ribosomal S6, phospho-S6 ribosomal protein, and Stat3. Immunostaining for phospho-4E-BP1 and phospho-Stat3 was negative in the normal brain cortex. There was no significant difference in the expression of mTOR pathway proteins between cases with loss of either hamartin or tuberin and cases with preserved protein expression [Table 3]; [Figure 2]c,[Figure 2]e,[Figure 2]f,[Figure 2]g,[Figure 2]h,[Figure 2]i.
Table 3: Imunohistochemistry in cases of subependymal giant cell astrocytomas

Click here to view

Mutation analysis

Of the 20 cases, 5 (25%) showed pathogenic mutations in TSC genes [Table 4], of which 2 patients were known cases of TSC. Three cases showed point mutation in exon 15 of TSC1 gene, while two cases showed point mutation in exon 33 of TSC2 gene. All cases except one showing point mutation also showed loss of either tuberin or hamartin on immunohistochemistry (IHC). Polymorphisms were also identified solely in exon 33 of TSC2 gene.
Table 4: Results of mutation analysis with corresponding hamartin and tuberin expression

Click here to view

 » Discussion Top

The current WHO classification of central nervous system (CNS) tumors classifies SEGA as a slow-growing tumor (WHO grade I) of mixed glioneuronal lineage. Role of TSC1 and TSC2 in the molecular pathogenesis of TSC is well established.[13] However, it was only recently shown in studies that inactivating mutations in TSC1 and TSC2 are linked to hyperactivation of the mTOR pathway.[14],[15] To analyze the hypothesis that dysregulated mTOR signaling due to TSC mutation leads to SEGA, we performed IHC for tuberin and hamartin, as well as mTOR pathway markers in the present study. We found loss of hamartin and tuberin in 32% and 36% of SEGA, respectively. Loss of protein expression was seen in all the tumor components of SEGA. Simultaneous loss of hamartin and tuberin was a rare event, seen only in one case. Surprisingly, in two cases having neuronal and extraneuronal manifestations, and fulfilling the definite clinical diagnostic criteria for TSC, SEGA did not show immunoloss of tuberin or hamartin. Jozwiak et al., found loss of hamartin in all cases (9 of 9) and loss of tuberin in 67% of cases (6 of 9) with SEGA examined by them.[13] In another study, tuberin was absent in 55% of SEGA cases (6 of 11) in epithelioid and spindle cell components, while giant cells showed faint staining.[16] We found pathogenic mutations in 20% of SEGA analyzed, both in TSC-associated and non–TSC-associated cases, although we could not perform complete screening of all exons owing to the large size of the two genes. Mutations have been reported in almost all the exons of the TSC genes, and no mutation accounts for more than 2% of all mutations seen.[14] Comprehensive mutation studies in TSC patients have led to the detection of mutations in approximately 85% of patients studied.[17] Most mutations are located on exon 15 of TSC1 gene and exon 32 of TSC2 gene.[12] Mutations in exon 35–39 of TSC2 gene encoding GAP domain are associated with a higher frequency of neurological lesions.[12] In concordance with the aforementioned observations, we found mutations in exon 15 of TSC1 gene and exon 33 of TSC2 gene. Most cases with mutation showed loss of protein immunoexpression, except for a single mutated case that did not exhibit loss of either hamartin or tuberin. Most TSC1 mutations are point mutations that lead to the truncation and loss of protein, while TSC2 mutations are largely missense mutations, in-frame deletions and large rearrangements, which lead to premature termination.[17] It is possible that some mutations may produce an unstable or nonfunctional intact protein that may be detectable by IHC, as in our case. Although the “two-hit” mechanism of germline and somatic mutations has been proposed for tubers in TSC patients, studies have not shown convincing evidence of loss of heterozygosity in brain lesions, indicating preservation of one of two alleles.[18],[19] Hence, cases may show preserved protein expression although they may be having clinical manifestations of the disease, owing to synthesis of some protein product of the retained allele, which may not be functional. This should be kept in mind while using hamartin or tuberin as surrogate markers for mutation testing or for diagnosing SEGA on small biopsies.

mTOR is a 280-kDa serine/threonine protein kinase that regulates cell growth, ribosome biogenesis, and autophagy, and is composed of two complexes: mTORC1, which is rapamycin-sensitive, and mTORC2, which is rapamycin-insensitive.[20] Disruption of the mTOR pathway has been implicated in various diseases, such as diabetes, obesity, neurodegenerative disorders, as well as cancers, including gliomas.[21],[22] Recent studies have shown mTOR to play a pivotal role in brain development, regulation of neuronal size and its morphology, dendrite formation, and axon elongation.[21] Experiments in mouse models and cultured mammalian cells lacking either TSC1 or TSC2 have demonstrated constitutive high-level phosphorylation of p70S6 kinase, 4E-BP1, and Stat3.[8],[14],[23] Ribosomal S6 protein is phosphorylated by these kinases, and recent studies have shown that phospho-S6 ribosomal protein immunoreactivity is a biomarker for hyperactive mTOR pathway.[14],[24] The present study showed overexpression of mTOR pathway proteins, viz., phoshpo-p70S6 kinase, S6 ribosomal protein, phospho-S6 ribosomal protein, and phospho-4E-BP1. Our study shows that SEGA are definitely associated with mTOR pathway activation, thus supporting the findings of two previous studies that demonstrated hyperactive mTOR pathway in SEGA.[12],[25] However, this activation could not be attributed to loss of TSC1 and TSC2. In normal cells, TSC1–TSC2 complex acts as an inhibitor of mTOR. Studies on Drosophila have led to placement of dTsc genes downstream of the Drosophila protein kinase, Akt.[26],[27] Morever, tuberin also acts as substrate for other upstream kinases, which have modulatory effects on downstream targets of tuberin.[28] Hence, it is possible that alterations in these kinases upstream of the TSC complex may lead to hyperactivation of mTOR pathway, leading to excessive cell proliferation in SEGA. However, distinctive neurological involvement suggests additional roles of hamartin–tuberin complex, which remain to be elucidated. Recent studies have also shown phospho-S6 ribosomal protein immunoreactivity in TSC, FCD IIB, and related malformative cortical lesions such as hemimegalencephaly and gangliogliomas, without any demonstrable loss of TSC gene activity.[29],[30],[31] Demonstration of robust expression of phosphorylated downstream mTOR signaling proteins in cases showing strong protein expression of tuberin and hamartin in other malformative lesions possibly suggests that all these lesions involve activation of the mTOR pathway. However, whether this hyperactivation is secondary to loss of TSC1 or TSC2 function or to some other intermediary molecular link needs to be investigated further.

An interesting feature of low-grade gliomas is their propensity to spontaneously stop growing or to even regress.[32] This slow growth rate and inability to progress to a higher histological grade may be attributed to the phenomenon of oncogene-induced senescence (OIS). Recent studies have demonstrated the role of the JAK/STAT3 signaling pathway in the induction of OIS, mediated by various cytokines.[33],[34] However, whether OIS is induced in SEGA is still unexplored. A few previous studies have shown increased expression of Stat3 in tubers.[12],[29] We performed IHC for Stat3 and phospho-Stat3 to elucidate the link between TSC2–mTOR signaling and Stat3 in regulating cell proliferation. While cytoplasmic Stat3 expression in giant cells was increased in all cases, only a small proportion of cases showed nuclear overexpression of phospho-Stat3. This is a significantly lower frequency of phospho-Stat3 expression as compared with a previous study on SEGAs and tubers that showed 100% positivity.[12],[29] However, this finding suggests that, while hyperactivation of mTOR pathway leads to dysregulated proliferation of cells, increased cytoplasmic Stat3 expression in these cells may be responsible for their ability to escape uncontrolled proliferation and thus limit tumor growth.

 » Conclusion Top

Mutations in TSC1 and TSC2 genes, and loss of proteins hamartin and tuberin play a definite role in the pathogenesis of SEGA. However, they are of limited value as diagnostic markers because loss of protein expression is not seen in all cases and analyzing TSC1 and TSC2 genes for mutation is not always feasible. mTOR pathway activation is a feature of SEGA, but its association with TSC gene alterations remains unclear and warrants further investigation to completely understand its role in the pathogenesis of these tumors.


We are thankful to Mr Pankaj and Mrs Kiran Rani for performing the immunohistochemistry.

Financial support and sponsorship


Conflicts of interest

None of the authors has any conflicts of interest to disclose.

 » References Top

Lopes MB, Wiestler OD, Stemmer-Rachamimov AO, Sharma MC. Tuberous sclerosis complex and subependymal giant cell astrocytomas. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon: IARC; 2007. p. 218-21.  Back to cited text no. 1
van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997;277:805-8.  Back to cited text no. 2
European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993;75:1305-15.  Back to cited text no. 3
Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: Revised clinical diagnostic criteria. J Child Neurol 1998;13:624-8.  Back to cited text no. 4
Park SH, Pepkowitz SH, Kerfoot C, De Rosa MJ, Poukens V, Wienecke R, et al. Tuberous sclerosis in a 20-week gestation fetus: Immunohistochemical study. Acta Neuropathol 1997;94:180-6.  Back to cited text no. 5
Gao X, Zhang Y, Arrazola P, Hino O, Kobayashi T, Yeung RS, et al. TSC tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol 2002;4:699-704.  Back to cited text no. 6
Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002;4:648-57.  Back to cited text no. 7
Onda H, Crino PB, Zhang H, Murphey RD, Rastelli L, Gould Rothberg BE, et al. Tsc2 null murine neuronal epithelial cells are a model for human tuber giant cells and show activation of an mTOR pathway. Mol Cell Neurosci 2002;21:561-74.  Back to cited text no. 8
Gomez MR, Sampson JR, Whittemore VH. Tuberous Sclerosis Complex. New York: Oxford University Press; 1999. p. 10-22.  Back to cited text no. 9
Kumar A, Kandt RS, Wolpert C, Roses AD, Pericak-Vance MA, Gilbert JR. A novel splice site mutation (156+1G->A) in the TSC2 gene. Hum Mutat 1997;9:64-5.  Back to cited text no. 10
Chan JA, Zhang H, Roberts PS, Jozwiak S, Wieslawa G, Lewin-Kowalik J, et al. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: Biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol 2004;63:1236-42.  Back to cited text no. 11
Sancak O, Nellist M, Goedbloed M, Elfferich P, Wouters C, Maat-Kievit A, et al. Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: Genotype–phenotype correlations and comparison of diagnostic DNA techniques in tuberous sclerosis complex. Eur J Hum Genet 2005;13:731-41.  Back to cited text no. 12
Jóźwiak S, Kwiatkowski D, Kotulska K, Larysz-Brysz M, Lewin-Kowalik J, Grajkowska W, et al. Tuberin and hamartin expression is reduced in the majority of subependymal giant cell astrocytomas in tuberous sclerosis complex consistent with a two-hit model of pathogenesis. J Child Neurol 2004;19:102-6.  Back to cited text no. 13
Kwiatkowski DJ. Tuberous sclerosis: From tubers to mTOR. Ann Hum Genet 2003;67:87-96.  Back to cited text no. 14
Crino PB. Molecular pathogenesis of tuber formation in tuberous sclerosis complex. J Child Neurol 2004;19:716-25.  Back to cited text no. 15
Henske EP, Wessner LL, Golden J, Scheithauer BW, Vortmeyer AO, Zhuang Z, et al. Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two-hit model for the pathogenesis of tuberous sclerosis tumors. Am J Pathol 1997;151:1639-47.  Back to cited text no. 16
Dabora SL, Jozwiak S, Franz DN, Roberts PS, Nieto A, Chung J, et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 2001;68:64-80.  Back to cited text no. 17
Crino PB, Aronica E, Baltuch G, Nathanson KL. Biallelic TSC gene inactivation in tuberous sclerosis complex. Neurology 2010;74:1716-23.  Back to cited text no. 18
Niida Y, Stemmer-Rachamimov AO, Logrip M, Tapon D, Perez R, Kwiatkowski DJ, et al. Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions. Am J Hum Genet 2001;69:493-503.  Back to cited text no. 19
Takei N, Nawa H. mTOR signaling and its roles in normal and abnormal brain development. Front Mol Neurosci 2014;7:28.  Back to cited text no. 20
Zoncu R, Efeyan A, Sabatini DM. mTOR: From growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011;12:21-35.  Back to cited text no. 21
Li XY, Zhang LQ, Zhang XG, Li X, Ren YB, Ma XY, et al. Association between AKT/mTOR signalling and malignancy grade of human gliomas. J Neurooncol 2011;103:453-8.  Back to cited text no. 22
Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg MK, Yeung RS, et al. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem 2002;277:30958-67.  Back to cited text no. 23
Crino PB. mTOR: A pathogenic signaling pathway in developmental brain malformations. Trends Mol Med 2011;17:734-42.  Back to cited text no. 24
Barrows BD, Rutkowski MJ, Gultekin SH, Parsa AT, Tıhan T. Evidence of ambiguous differentiation and mTOR pathway dysregulation in subependymal giant cell astrocytoma.Turk Patoloji Derg 2012;28:95-103.  Back to cited text no. 25
Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, et al. Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J Biol Chem 2000;277:35364-70.  Back to cited text no. 26
Krymskaya VP. Tumour suppressors hamartin and tuberin: Intracellular signalling. Cell Signal 2003;15:729-39.  Back to cited text no. 27
Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003;115:577-90.  Back to cited text no. 28
Baybis M, Yu J, Lee A, Golden JA, Weiner H, McKhann G 2nd, et al. mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Ann Neurol 2004;56:478-87.  Back to cited text no. 29
Lim KC, Crino PB. Focal malformations of cortical development: New vistas for molecular pathogenesis. Neuroscience 2013;252:262-76.  Back to cited text no. 30
Liu J, Reeves C, Michalak Z, Coppola A, Diehl B, Sisodiya SM, et al. Evidence of mTOR pathway activation in a spectrum of epilepsy-associated pathologies. Acta Neuropathol Commun 2014;2:71.  Back to cited text no. 31
Gunny RS, Hayward RD, Phipps KP, Harding BN, Saunders DE. Spontaneous regression of residual low-grade cerebellar pilocytic astrocytomas in children. Pediatr Radiol 2005;35:1086-91.  Back to cited text no. 32
Kojima H, Inoue T, Kunimoto H, Nakajima K. IL-6-STAT3 signalling and premature senescence. JAKSTAT 2013;2:e25763-6.  Back to cited text no. 33
Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: A leading role for STAT3. Nat Rev Cancer 2009;9:798-809.  Back to cited text no. 34


  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4]

This article has been cited by
1 Development of hypomelanotic macules is associated with constitutive activated mTORC1 in tuberous sclerosis complex
Lisbeth Birk Møller,Bitten Schönewolf-Greulich,Thomas Rosengren,Lasse Jonsgaard Larsen,John R. Ostergaard,Mette Sommerlund,Caroline Ostenfeldt,Brian Stausbøl-Grøn,Karen Markussen Linnet,Pernille Axél Gregersen,Uffe Birk Jensen
Molecular Genetics and Metabolism. 2017; 120(4): 384
[Pubmed] | [DOI]


Print this article  Email this article
Online since 20th March '04
Published by Wolters Kluwer - Medknow