Gene interactions and pathways from curated databases and text-mining
Stem Cells 2008, PMID: 18556508

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

Kim, Bong Cho; Ryu, Min Sook; Oh, S Paul; Lim, In Kyoung

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.

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Text Mining Data

Akt ⊣ mitogen activated protein kinase: " Furthermore, mitogen activated protein kinase 1/2 inhibitor or knockdown of Erk1 could restore activation of Akt and downregulate mTOR "

Akt ⊣ Erk1: " Furthermore, mitogen activated protein kinase 1/2 inhibitor or knockdown of Erk1 could restore activation of Akt and downregulate mTOR "

Akt ⊣ mitogen activated protein kinase 1/2: " Furthermore, mitogen activated protein kinase 1/2 inhibitor or knockdown of Erk1 could restore activation of Akt and downregulate mTOR "

Akt → mTOR: " 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 "

Akt → p-Erk1/2: " 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 "

Akt → p-Erk1/2: " 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 "

mTOR → p-Erk1/2: " 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 "

mTOR → p-Erk1/2: " 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 "

Manually curated Databases

No curated data.