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MAPK3 MTOR (1 - 2 of 2)
PMID: 18556508
TIS21/(BTG2) negatively regulates estradiol-stimulated expansion of hematopoietic stem cells by derepressing Akt phosphorylation and inhibiting mTOR signal transduction.
... constitutive activation of mTOR via ... -induced p-Erk1/2, ...   (details)

MAPK3 MTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 18556508

TIS21/(BTG2) negatively regulates estradiol-stimulated expansion of hematopoietic stem cells by derepressing Akt phosphorylation and inhibiting mTOR signal transduction.
Source

Stem cells (Dayton, Ohio; September 2008)

Abstract

TIS21/ (BTG2) negatively regulates estradiol-stimulated expansion of hematopoietic stem cells by derepressing Akt phosphorylation and inhibiting mTOR signal transduction. It has been known that 12-O-tetradecanoyl phorbol-13-acetate-inducible sequence 21 (TIS21), ortholog of human B-cell translocation gene 2, regulates expansions of stage-specific thymocytes and hematopoietic progenitors. In the present study, lineage-negative (Lin (-)) /stem cell antigen-1-positive (Sca-1+) /c-Kit+ (LSK) cell content was significantly elevated in bone marrow (BM) of TIS21-knockout (TIS21 (-/-)) female mice, suggesting 17beta-estradiol (E (2)) -regulated progenitor expansion. E (2) induced DNA synthesis and cell proliferation of mouse embryonic fibroblasts (MEFs) isolated from TIS21 (-/-) mice, but not wild type (WT). In contrast to WT, E (2) failed to activate protein kinase B (Akt) in the TIS21 (-/-) MEFs, independent of extracellular signal-regulated kinase 1/2 (Erk1/2) activation. Despite attenuation of Akt activation, mammalian target of rapamycin (mTOR) was constitutively activated in the TIS21 (-/-) MEFs. Furthermore, mitogen-activated protein kinase 1/2 inhibitor or knockdown of Erk1 could restore activation of Akt and downregulate mTOR. Immunoprecipitation showed Akt preferentially bound to phosphorylated Erk1/2 (p-Erk1/2) in TIS21 (-/-) cells, but reconstitution of TIS21 inhibited their interaction. E (2) -injected TIS21 (-/-) male mice also increased LSK cells in BM. Taken together, expansion of hematopoietic progenitors in TIS21 (-/-) female mice might be through inhibition of Akt activation, and constitutive activation of mTOR via preferential binding of TIS21 to E (2) -induced p-Erk1/2, compared with that of Akt. Our results suggest that TIS21 plays a pivotal role in maintaining the hematopoietic stem cell compartment and hematopoiesis.

PMID: 21947203
Targeting autophagy enhances BO-1051-induced apoptosis in human malignant glioma cells.
... of Akt/mTOR and activation of Erk1/2.   (details)

MAPK3 MTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 21947203

Targeting autophagy enhances BO-1051-induced apoptosis in human malignant glioma cells.
Source

Cancer chemotherapy and pharmacology (March 2012)

Abstract

Targeting autophagy enhances BO-1051-induced apoptosis in human malignant glioma cells. [PURPOSE] BO-1051 is an N-mustard derivative that is conjugated with DNA-affinic 9-anilinoacridine. Since BO-1051 was reported to have strong anticancer activity, we investigated the effect and underlying mechanism of BO-1051 in human glioma cell lines. [METHODS] Human glioma cell lines U251MG and U87MG were studied with BO-1051 or the combination of BO-1051 and autophagic inhibitors. Growth inhibition was assessed by MTT assay. Apoptosis was measured by annexin V staining followed by flow cytometry and immunoblotting for apoptosis-related molecules. Induction of autophagy was detected by acridine orange labeling, electron microscopy, LC3 localization and its conversion. Transfection of shRNA was used to determine the involvement of Beclin1 in apoptotic cell death. [RESULTS] MTT assay showed that BO-1051 suppressed the viability of four glioma cell lines (U251MG, U87MG, GBM-3 and DBTRG-05MG) in a dose-dependent manner. The IC (50) values of BO-1051 for the glioma cells were significantly lower than the values for primary neurons cultures and normal fibroblast cells. Moreover, BO-1051 not only induced apoptotic cell death, but also enhanced autophagic flux via inhibition of Akt/mTOR and activation of Erk1/2. Importantly, suppression of autophagy by 3-methyladenine or bafilomycin A1 significantly increased BO-1051-induced apoptotic cell death in U251MG and U87MG cells. In addition, the proportion of apoptotic cells after BO-1051 treatment was enhanced by co-treatment with shRNA against Beclin1. [CONCLUSIONS] BO-1051 induced both apoptosis and autophagy, and inhibition of autophagy significantly augmented the cytotoxic effect of BO-1051. Thus, a combination of BO-1051 and autophagic inhibitors offers a potentially new therapeutic modality for the treatment of malignant glioma.