The Minimal Epo Receptor Allele, EpoR-H, Regulates ERK1,2, (But Not JNKs or p70S6K), and Induces Pim-1, SOCS3 and Oncostatin-M (But Not BcL-XL) in Primary Erythroblasts

Autor: Estelle Houde, Bethany Cuetara, Madhu P. Menon, Melanie Ufkin, Jing Fang, Don M. Wojchowski, Olga Bogacheva, Vinit Karur, Oleg Bogachev
Rok vydání: 2005
Předmět:
Zdroj: Blood. 106:3559-3559
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood.v106.11.3559.3559
Popis: In studies of core Epo receptor signals that are necessary-and-sufficient for erythroblast development, we have shown that an EpoR-PY343-Stat5 axis is required for efficient erythropoiesis during anemia. This involved analyses of knocked-in truncated Epo receptor alleles that retain only a PY343 Stat5 binding site (EpoR-H allele), or lack all cytoplasmic PY motifs (EpoR-HM allele). Presently we have analyzed core signaling capacities of these receptor forms (and the wt-EpoR) in purified developmentally-staged marrow- derived erythroblasts. Analyses of JNKs, p70s6K and ERKs revealed that JNK and p70s6K activation is mediated by non-essential C-terminal EpoR domains. ERKs, in contrast, remained coupled to EpoR-H and EpoR-HM forms. EpoR-H/PY343/Stat5 response genes that might support EpoR-H’s wild-type activity next were analyzed. Despite evidence for Stat5 binding at a Bcl-x intron-1 element, no significant Epo-induction of Bcl-x transcripts was detected for any EpoR allele. In contrast, Pim-1, oncostatin-M and SOCS-3 were induced multi-fold in wt-EpoR and EpoR-H, but not EpoR-HM erythroblasts (and for EpoR-HM, no activation of Stat-5, -1 or-3 was detectable). In addition, receptor cross-talk analyses revealed that Kit selectively modulates EpoR-PY343-Stat5- dependent SOCS-3 and oncostatin-M transcription, and enhances Pim-1 expression several-fold via apparent post-transcriptional mechanisms. Epo action therefore is proposed to depend primarily on the regulation of ERKs, Pim-1 and possibly oncostatin-M (but not JNKs, p70S6K or Bcl-x).
Databáze: OpenAIRE
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