Tuberous Sclerosis Complex 2 Gene Product Interacts with Human SMAD Proteins

Birchenall-Roberts, Maria C.; Fu, Tao; Bang, Ok‐Sun; Dambach, Michael; Resau, James H.; Sadowski, Cari; Bertolette, Daniel C.; Lee, Hojae; Kim, Seong‐Jin; Ruscetti, Francis W.

doi:10.1074/jbc.m402790200

Cited by 33 publications

(16 citation statements)

References 38 publications

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“…Several molecules critical for cell cycle progression have recently been shown to interact with TSC1 or TSC2 in mammalian cells, including: D-type cyclins (Zacharek et al, 2005), polo-like kinase 1 (Astrinidis et al, 2006) and the cyclin-dependent kinase inhibitor p27 , These findings are not surprising; well before the mammalian homolog of TOR was discovered, it was surmised that whatever molecule rapamycin targeted must have a significant effect on cell cycle progression, given the profound effects of rapamycin treatment in T lymphocytes and in yeast (Sabers et al, 1995). Other growth regulatory proteins that have been shown to affect mTOR via TSC1/2 include the SMAD (mothers against decapentaplegic) proteins (Birchenall-Roberts et al, 2004), the focal adhesion kinase interacting protein FIP200 (Gan et al, 2005), the estrogen receptor (Finlay et al, 2004) and many more than space will allow us to mention in detail. As mouse models have been dramatically successful in demonstrating the relevance of insulinand Akt-mediated mTOR activation, future study of the many biochemical observations listed above will require similar experiments to be performed.…”

Section: Negative and Positive Feedbackmentioning

confidence: 99%

Upstream of the mammalian target of rapamycin: do all roads pass through mTOR?

2006

Oncogene

348

309

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The mammalian target of rapamycin (mTOR) is a serine/ threonine kinase that controls many aspects of cellular physiology, including transcription, translation, cell size, cytoskeletal organization and autophagy. Recent advances in the mTOR signaling field have found that mTOR exists in two heteromeric complexes, mTORC1 and mTORC2. The activity of mTORC1 is regulated by the integration of many signals, including growth factors, insulin, nutrients, energy availability and cellular stressors such as hypoxia, osmotic stress, reactive oxygen species and viral infection. In this review we highlight recent advances in the mTOR signaling field that relate to how the two mTOR complexes are regulated, and we discuss stress conditions linked to the mTOR signaling network that have not been extensively covered in other reviews. Given the diversity of signals that have been shown to impinge on mTOR, we also speculate on other signaltransduction pathways that may be linked to mTOR in the future.

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Section: Negative and Positive Feedbackmentioning

confidence: 99%

Upstream of the mammalian target of rapamycin: do all roads pass through mTOR?

2006

Oncogene

348

309

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“…Interestingly, depletion of SMAD2, but not SMAD3, significantly abolished the pSMAD2-mediated increases in cell-cycle inhibitor, p27 (Fig. 3) [12,20,47,48,49]. Moreover, in a MTT assay, pSMAD2 activation, but not pSMAD3 activation, seemed to inhibit the growth of GBM cells in responsive to TGFβ1 stimulation (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The control of p27 by pSMAD2 has been well-established [12,20,47,48,49]. Since pSMAD2 forms a complex with SMAD4 and then translocates into the nucleus to allow its direct binding to DNA to modulate gene expression, e.g.…”

Section: Discussionmentioning

confidence: 99%

Nuclear SMAD2 Restrains Proliferation of Glioblastoma

Ran²

2015

Cell Physiol Biochem

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Aims: Although TGFβ receptor signaling has been shown to play a role in regulation of the growth and metastasis of glioblastoma multiforme (GBM), the downstream pathway through either SMAD2 or SMAD3 has not been elucidated. In this study, we investigate whether nuclear SMAD2 can restrain the proliferation of glioblastoma. Methods: A total of 23 resected specimens from GBM patients were collected for SMAD2 detection. Human GBM cell line A172, U87mg, D341m and Hs683 were maintained in Dulbecco's modified Eagle's medium and transfected with SMAD2 and SMAD3 shRNA plasmids. Gene expression was detected by RT-qPCR and Western and cell growth were detected by MTT assay. Results: Our results showed that the phosphorylated SMAD2 (pSMAD2, the nuclear and functional form of SMAD2) levels in GBM were significantly lower than the paired normal brain tissue in patients. Depletion of SMAD2, but not SMAD3, significantly abolished the inhibitory effects of TGFβ1 on the growth of GBM cells, possibly through pSMAD2-mediated increases in cell-cycle inhibitor, p27. Conclusion: Our data suggest that TGFβ/SMAD2 signaling cascades restrains growth of GBM.

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“…Smad3 interacts with Interferon Regulatory Factor-7 (IRF-7), an essential transcription factor for interferon-mediated-a and -~induction, to activate interferon-f transcription (163), and the Tuberous Sclerosis Complex 2 (TSC2) tumor suppressor gene, in which the amino-terminal region of tuberin interacts specifically with the MH2 domain of Smad2 and Smad3 proteins to regulate TGF-~ responsive genes such as p21Cipl (164). FoxO Forkhead transcription factors act as signal transducers at the confluence of Smad, phosphatidylinositol-3 (PI-3) kinase, and telencephalic development factor FoxGl signaling pathways (165).…”

Section: Modulators Of Smad Signalingmentioning

confidence: 99%

Component Hardware for Transforming Growth Factor-β Signal Transduction: TGF-β Ligands, TGF-β Receptors, and Smads

Jakowlew

2008

Transforming Growth Factor-Β in Cancer Therapy, Volume I

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Tuberous Sclerosis Complex 2 Gene Product Interacts with Human SMAD Proteins

Cited by 33 publications

References 38 publications

Upstream of the mammalian target of rapamycin: do all roads pass through mTOR?

Upstream of the mammalian target of rapamycin: do all roads pass through mTOR?

Nuclear SMAD2 Restrains Proliferation of Glioblastoma

Component Hardware for Transforming Growth Factor-β Signal Transduction: TGF-β Ligands, TGF-β Receptors, and Smads

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