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Activation of extracellular signal-regulated kinases ERK1 and ERK2 induces Bcl-xL up-regulation via inhibition of caspase activities in erythropoietin signaling.
J Cell Physiol. 2003 May; 195(2):290-7.JC

Abstract

Erythropoietin (EPO) can rescue erythroid cells from apoptosis during erythroid development, leading to red cell production. However, the detailed mechanism of how EPO protects erythroid cells from apoptosis is still open to question. To address this problem, we used a human EPO-dependent leukemia cell line UT-7/EPO and normal erythroid progenitor cells. After deprivation of EPO, UT-7/EPO cells underwent apoptosis, accompanied by down-regulation of the Bcl-xL protein. In addition, the cleaved products of caspase-3, p11 and p21, and a few cleaved forms of inhibitor of caspase-activated DNase (ICAD) were detected in these cells. When the cells were pre-treated with the pancaspase inhibitor Z-VAD-FMK, the ratio of apoptotic cells was significantly reduced, suggesting that EPO protects the UT-7/EPO cells from apoptosis via inhibition of caspase activities. When an MEK 1/2 inhibitor U0126 inhibited activities of extracellular signal-regulated kinases (ERKs), the expression of Bcl-xL protein was down-regulated and subsequently apoptosis was induced. Interestingly, Z-VAD-FMK blocked U0126-induced down-regulation of Bcl-xL protein and apoptosis, strongly suggesting that Bcl-xL expression is regulated by caspases which lies downstream of ERK activation pathway in EPO signaling. Importantly, these findings were also observed in normal erythroid progenitor cells. In conclusion, the activation of ERKs by EPO up-regulates Bcl-xL expression via inhibition of caspase activities, resulting in the protection of erythroid cells from apoptosis.

Authors+Show Affiliations

Division of Hematology, Department of Medicine, Jichi Medical School, Tochigi, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12652655

Citation

Mori, Masaki, et al. "Activation of Extracellular Signal-regulated Kinases ERK1 and ERK2 Induces Bcl-xL Up-regulation Via Inhibition of Caspase Activities in Erythropoietin Signaling." Journal of Cellular Physiology, vol. 195, no. 2, 2003, pp. 290-7.
Mori M, Uchida M, Watanabe T, et al. Activation of extracellular signal-regulated kinases ERK1 and ERK2 induces Bcl-xL up-regulation via inhibition of caspase activities in erythropoietin signaling. J Cell Physiol. 2003;195(2):290-7.
Mori, M., Uchida, M., Watanabe, T., Kirito, K., Hatake, K., Ozawa, K., & Komatsu, N. (2003). Activation of extracellular signal-regulated kinases ERK1 and ERK2 induces Bcl-xL up-regulation via inhibition of caspase activities in erythropoietin signaling. Journal of Cellular Physiology, 195(2), 290-7.
Mori M, et al. Activation of Extracellular Signal-regulated Kinases ERK1 and ERK2 Induces Bcl-xL Up-regulation Via Inhibition of Caspase Activities in Erythropoietin Signaling. J Cell Physiol. 2003;195(2):290-7. PubMed PMID: 12652655.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of extracellular signal-regulated kinases ERK1 and ERK2 induces Bcl-xL up-regulation via inhibition of caspase activities in erythropoietin signaling. AU - Mori,Masaki, AU - Uchida,Mie, AU - Watanabe,Tomoko, AU - Kirito,Keita, AU - Hatake,Kiyohiko, AU - Ozawa,Keiya, AU - Komatsu,Norio, PY - 2003/3/26/pubmed PY - 2003/5/31/medline PY - 2003/3/26/entrez SP - 290 EP - 7 JF - Journal of cellular physiology JO - J. Cell. Physiol. VL - 195 IS - 2 N2 - Erythropoietin (EPO) can rescue erythroid cells from apoptosis during erythroid development, leading to red cell production. However, the detailed mechanism of how EPO protects erythroid cells from apoptosis is still open to question. To address this problem, we used a human EPO-dependent leukemia cell line UT-7/EPO and normal erythroid progenitor cells. After deprivation of EPO, UT-7/EPO cells underwent apoptosis, accompanied by down-regulation of the Bcl-xL protein. In addition, the cleaved products of caspase-3, p11 and p21, and a few cleaved forms of inhibitor of caspase-activated DNase (ICAD) were detected in these cells. When the cells were pre-treated with the pancaspase inhibitor Z-VAD-FMK, the ratio of apoptotic cells was significantly reduced, suggesting that EPO protects the UT-7/EPO cells from apoptosis via inhibition of caspase activities. When an MEK 1/2 inhibitor U0126 inhibited activities of extracellular signal-regulated kinases (ERKs), the expression of Bcl-xL protein was down-regulated and subsequently apoptosis was induced. Interestingly, Z-VAD-FMK blocked U0126-induced down-regulation of Bcl-xL protein and apoptosis, strongly suggesting that Bcl-xL expression is regulated by caspases which lies downstream of ERK activation pathway in EPO signaling. Importantly, these findings were also observed in normal erythroid progenitor cells. In conclusion, the activation of ERKs by EPO up-regulates Bcl-xL expression via inhibition of caspase activities, resulting in the protection of erythroid cells from apoptosis. SN - 0021-9541 UR - https://www.unboundmedicine.com/medline/citation/12652655/Activation_of_extracellular_signal_regulated_kinases_ERK1_and_ERK2_induces_Bcl_xL_up_regulation_via_inhibition_of_caspase_activities_in_erythropoietin_signaling_ L2 - https://doi.org/10.1002/jcp.10245 DB - PRIME DP - Unbound Medicine ER -