Tuberin activates the proapoptotic molecule BAD

Freilinger, Angelika; Rosner, Margit; Krupitza, Georg; Nishino, Mari; Lubec, Gert; Korsmeyer, Stanley J.; Hengstschläger, Markus

doi:10.1038/sj.onc.1209660

Cited by 40 publications

(37 citation statements)

References 43 publications

(73 reference statements)

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“…Recently, we reported that in selection experiments as well as in transient approaches ectopic expression of wild-type TSC2 induces apoptosis (Freilinger et al, 2006). Here, flowcytometric analyses of the amount of subG1 cells, detection of caspase 3 cleavage and PARP cleavage by western blotting confirmed this potential of tuberin (Figures 2a-d).…”

Section: Ras Negatively Affects Tuberin-induced Apoptosissupporting

confidence: 64%

“…Luciferase activities are indirect indicators for apoptosis. In cell populations with more luciferase activity in the lysates, more cells are viable and less apoptosis is present (see for example, Harada et al, 2001;Wohlfart et al, 2004;Freilinger et al, 2006). Ras-mediated cell survival was also detectable performing luciferase assays (Figure 1e).…”

Section: Resultsmentioning

confidence: 93%

“…In the recent past we have used the tumor-derived HeLa cell line to demonstrate tuberin's proapoptotic function via regulating p70S6K (Freilinger et al, 2006). Ectopic expression of mutationally activated Ras is a well-established and widely used experimental approach to mimic the situation of tumor cells harboring constitutively active Ras, which is insensitive to negative regulation by GTPase-activating proteins.…”

Section: Resultsmentioning

confidence: 99%

“…These effects on BAD phosphorylation cause an upregulation of the interaction of BAD/BCL-2 and BAD/BCL-X L leading to induction of apoptosis. These findings demonstrated that depending on the exogenous triggers and on the cellular background tuberin is a positive regulator of apoptosis (Freilinger et al, 2006).…”

Section: Introductionmentioning

confidence: 83%

“…To analyse the functional interaction of tuberin and Ras in regulating apoptosis induced by another stimulus, we made use of staurosporine, another well-known inducer of apoptosis (see for example, Arrebola et al, 2005;Freilinger et al, 2006). We found that upon reintroduction of TSC2 into TSC2À/À cells Ras more efficiently mediates cell survival also over staurosporineinduced apoptosis (Figure 7c; P>0.05; Student's t-test).…”

Section: Ras Mediates Cell Survival By Regulating Tuberinmentioning

confidence: 94%

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Ras mediates cell survival by regulating tuberin

et al. 2007

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Mutational activation of Ras promotes oncogenesis by controlling cell cycle regulation and cell survival. Rasmediated activation of both, the PI3K/AKT pathway and the MEK/ERK pathway, can trigger downregulation of the function of tuberin to block the activities of mTOR and p70S6K. Here we demonstrate that Ras-induced cell survival is accompanied by upregulation of p70S6K activity. Ras harbors the potential to negatively affect tuberin-induced apoptosis and p70S6K inactivation. These effects of Ras were found to depend on its potential to regulate the MEK/ERK pathway. Experiments using tuberin-negative fibroblasts revealed that the potential of Ras to counteract apoptosis depends on functional tuberin. Taken together, we provide evidence that the function of Ras to trigger inactivation of tuberin plays a major role in the regulation of cell survival upon mutational activation of the oncogene Ras. This is the first description of a functional interaction between the tumor suppressor tuberin and the oncogene Ras in regulating apoptosis.

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Section: Ras Negatively Affects Tuberin-induced Apoptosissupporting

confidence: 64%

Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 83%

Section: Ras Mediates Cell Survival By Regulating Tuberinmentioning

confidence: 94%

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Ras mediates cell survival by regulating tuberin

et al. 2007

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FMRP regulates endothelial cell proliferation and angiogenesis via the miR‐181a‐CaM‐CaMKII pathway

Zhao

Wang

Meng

et al. 2018

Cell Biology International

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RNA binding proteins (RBPs) and microRNAs have emerged as crucial post-transcriptional regulators of gene expression. Although the role of Fragile X mental retardation protein (FMRP) has been well studied in the brain, the function of FMRP in endothelial cells remains unknown. In our study, we showed that FMRP controlled human umbilical vein endothelial cells (HUVECs) proliferation and angiogenesis via the miR-181a-mediated calmodulin (CaM)/CaMKII pathway. The knockdown of FMRP induced miR-181a expression and contributed to endothelial cell proliferation and angiogenesis. Furthermore, we identified CaM as a downstream target of miR-181a in endothelial cells. Additionally, tumor necrosis factor-ɑ (TNF-ɑ) treatment specifically decreased the activity of the CaM/CaMKII pathway through the dephosphorylation of FMRP and upregulation of miR-181a. Finally, the overexpression of constitutively phosphorylated FMRP rescued the TNF-ɑ-impaired endothelial cell proliferation and angiogenesis by activating the CaM/CaMKII pathway and downregulating miR-181a, which suggested there was a pivotal role of FMRP in vascular integrity in response to inflammatory stimuli. Thus, our study supports a novel function and mechanism involving FMRP and the miR-181a-CaM-CaMKII pathway may be a therapeutic target for protecting against inflammation-induced vascular diseases.

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Non‐canonical functions of the tuberous sclerosis complex‐Rheb signalling axis

Neuman

Henske

2011

EMBO Mol Med

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The protein products of the tuberous sclerosis complex (TSC) genes, TSC1 and TSC2, form a complex, which inhibits the small G-protein, Ras homolog enriched in brain (Rheb). The vast majority of research regarding these proteins has focused on mammalian Target of Rapamycin (mTOR), a target of Rheb. Here, we propose that there are clinically relevant functions and targets of TSC1, TSC2 and Rheb, which are independent of mTOR. We present evidence that such non-canonical functions of the TSC-Rheb signalling network exist, propose a standard of evidence for these non-canonical functions, and discuss their potential clinical and therapeutic implications for patients with TSC and lymphangioleiomyomatosis (LAM).

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Tuberin activates the proapoptotic molecule BAD

Cited by 40 publications

References 43 publications

Ras mediates cell survival by regulating tuberin

Ras mediates cell survival by regulating tuberin

FMRP regulates endothelial cell proliferation and angiogenesis via the miR‐181a‐CaM‐CaMKII pathway

Non‐canonical functions of the tuberous sclerosis complex‐Rheb signalling axis

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