Disease relevance of N-Formyl-T-P-methoxystyrilamine

• The tuberous sclerosis complex gene-2 (TSC2) on chromosome 16 encodes the tumor suppressor protein tuberin [1].
• Loss of tuberin from cerebral tissues with tuberous sclerosis and astrocytoma [2].
• While the TSC2 transcript is widely expressed primarily within neurons, tuberin is demonstrable primarily within dysplastic/cytomegalic cells of the cortex and subependymal hamartomas/SEGAs [3].
• Reduced or absent tuberin was observed in 2 of 6 (33%) ependymomas analyzed [4].
• Tuberin was abundant in the gray matter of normal cerebra, but was undetectable in the subependymal astrocytomas from 3 patients with tuberous sclerosis [2].

Psychiatry related information on N-Formyl-T-P-methoxystyrilamine

• Further characterization of the roles of hamartin and tuberin will provide potential therapeutic avenues to treat seizures, mental retardation, and tumor growth in TSC [5].
• Here we report that tuberin protein levels are decreased in the frontal cortex of patients with Alzheimer's disease [6].

High impact information on N-Formyl-T-P-methoxystyrilamine

• Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo [7].
• We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines [7].
• Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway [7].
• Tuberin-dependent membrane localization of polycystin-1: a functional link between polycystic kidney disease and the TSC2 tumor suppressor gene [8].
• These data identify tuberin as a determinant of polycystin-1 functional localization and, potentially, ADPKD severity [8].

Chemical compound and disease context of N-Formyl-T-P-methoxystyrilamine

• PGE2 also phosphorylated Akt and tuberin in Ishikawa endometrial adenocarcinoma cells, leading to a reduction in expression of total tuberin protein [9].
• The methylthio, ethoxy, and methyl analogues 4e, 4j, and 4t were about twice as active as tuberin against Mycobacterium phlei [10].
• Estrogen action and tuberin function has been suggested to play a crucial role in the proliferation of lung smooth muscle-like cells and/or myofibroblasts in pulmonary lymphangioleiomyomatosis (LAM) [11].

Biological context of N-Formyl-T-P-methoxystyrilamine

• Loss of tuberin, the product of TSC2 gene, increases mammalian target of rapamycin (mTOR) signaling, promoting cell growth and tumor development [12].
• At the cellular level, restoration of tuberin expression caused morphological changes characterized by enlargement of the cells and increased contact inhibition [13].
• An interaction of hamartin and tuberin can be detected in every phase of the cell cycle [14].
• Here we show that the region of homology between tuberin and human rap1GAP and the murine GAP mSpa1 is more extensive than previously reported and spans approximately 160 amino acid residues encoded within exons 34-38 of the TSC2 gene [15].
• Intriguingly, the TSC2 product, tuberin, has an area of sequence homology with the GTPase activating protein rap1GAP, suggesting a possible mechanism for its role in regulating cellular growth [16].

Anatomical context of N-Formyl-T-P-methoxystyrilamine

• In response to growth signals, tuberin is phosphorylated by AKT and translocates to the cytosol, relieving Rheb repression [12].
• In normal Rat1 fibroblasts, conditional overexpression of tuberin also suppressed colony formation and cell growth in vitro [13].
• Individual cells within subependymal giant cell astrocytomas (SEGAs) and hamartomas from TSC patients expressed moderate to high levels of TSC2 transcript and tuberin [3].
• Tuberin, the protein product of the tuberous sclerosis complex-2 (TSC2) tumor suppressor gene, has been shown to directly inhibit cell growth and is expressed at high levels in normal central nervous system neurons and astrocytes [4].
• We show here that Esrom has E3 ligase activity and modulates the amount of phosphorylated Tuberin, a tumor suppressor, in growth cones [17].

Associations of N-Formyl-T-P-methoxystyrilamine with other chemical compounds

• In this study, we showed that tuberin is phosphorylated at serine and tyrosine residues in response to serum and other factors, and it undergoes serial phosphorylation that can be detected by differences in electrophoretic mobilities [18].
• Finally, overexpression of Rheb, a downstream target of Tuberin function and a positive upstream effector of mTOR, reverses the effect of dexamethasone on phosphorylation of mTOR substrates [19].
• These data suggest that PGE2 signaling may promote endometrial tumorigenesis by inactivation of tuberin after its phosphorylation via the Akt signaling pathway [9].
• In cells lacking tuberin, most of the endogenous caveolin-1 was displaced from the plasma membrane to a Brefeldin-A-sensitive, post-Golgi compartment distinct from the endosome and lysosome [20].
• We examined the expression of tuberin and tuberous sclerosis complex gene 1 product hamartin, proteins of the insulin-signaling pathway, steroid receptors and some of their cofactors, and human mobility group gene A2 by immunohistochemistry [21].

Gene context of N-Formyl-T-P-methoxystyrilamine

• Tuberin and hamartin form a complex that inhibits signaling by the mammalian target of rapamycin (mTOR), a critical nutrient sensor and regulator of cell growth and proliferation [22].
• Hamartin and tuberin interaction with the G2/M cyclin-dependent kinase CDK1 and its regulatory cyclins A and B [23].
• In contrast, exercise caused no change in phosphorylation of either Akt/PKB or tuberin [24].
• Together, our data unveil a regulatory mechanism by which the Ras/MAPK and PI3K pathways converge on the tumor suppressor tuberin to inhibit its function [22].
• Supporting this notion, TSC patient-derived Tuberin GAP domain mutants were unable to inactivate Rheb in vivo [25].

Analytical, diagnostic and therapeutic context of N-Formyl-T-P-methoxystyrilamine

• We used immunohistochemistry with antibodies against p-PDK1 (S241), p-Akt (S473), p-tuberin (T1462), p-p70(S6K) (T389), p-p70(S6K) (T229) and phalloidin-staining to analyze stress fiber formation in balloon cells of FCD(IIb) (n = 23) compared with cortical tuber giant cells (n = 5) and adjacent normal CNS tissue as control [26].
• These observations suggest either that tuberin expression is controlled at the level of both transcription and translation or the antibody and in-situ hybridization recognize different splice variants of the TSC2 gene [3].
• We have generated antisera against the N-terminal and C-terminal portions of tuberin, and these antisera specifically recognize a 180-kDa protein in immunoprecipitation and immunoblotting analyses [27].
• Moreover, conventional and confocal immunofluorescence demonstrated co-localization of tuberin with Rap1, which has previously been localized to the Golgi apparatus [28].
• Indirect immunofluorescence of tuberin in various cultured cell lines revealed a punctate, mostly perinuclear staining pattern [28].

References