IntroductionErythropoiesis is mainly regulated by the kidney-produced hormone erythropoietin (Epo), which is absolutely required for the survival and proliferation of erythroid progenitors and their terminal differentiation to red cells. 1 The Epo receptor (EpoR) is a type 1 transmembrane protein that belongs to the class 1 cytokine receptor family. Its expression level in erythroid cells is low whatever the differentiation stage and even the most Epo-sensitive cells, colony-forming units erythroid (CFU-Es), or proerythroblasts express less than 1000 EpoRs per cell at their surface. 2 In the absence of Epo, EpoR is believed to be homodimeric, in which each dimer protein is constitutively associated with a Janus kinase-2 (Jak-2) tyrosine-kinase molecule. Epo binding modifies the organization of the receptor complex leading to Jak-2 activation. Association between Jak-2 and the EpoR occurs during the receptor maturation process, most likely before EpoR leaves the endoplasmic reticulum, and is essential for expression of the receptor at the cell surface. 3 However, the mechanisms that control the maturation and the transport of the EpoR to the cell surface remain largely unknown. Indeed, the number of cell surface EpoRs is not related to the synthesis level of this protein and most of these molecules accumulate in the endoplasmic reticulum in EpoRoverexpressing cells. 4 Both functional and direct evidence also suggests that unidentified proteins are associated with EpoR on the cell surface. In particular, chemical cross-linking of radiolabeled Epo to cell surface erythroid cells has frequently revealed the presence of 2 additional proteins with apparent molecular masses of 85 and 100 kDa in the EpoR complex. 2,5-8 Unfortunately, because of the low expression level of the EpoR, these proteins could never be identified up to now. The dramatic progress that has been recently introduced by the application of mass spectrometry methods to protein analysis led us to address the question of the identity of the EpoR-associated proteins.Here, we have purified the EpoR complex from UT7 erythroleukemic cells that express endogenous EpoRs to identify EpoRassociated proteins. Mass spectrometry analysis of the purified proteins revealed the presence of the type 2 transferrin receptor (TfR2) in the EpoR complex.Mammals express 2 transferrin receptors that share similar overall structures but possess specific functions. Most cells including erythroid precursors internalize iron from plasma diferric transferrin through the ubiquitously expressed transferrin receptor 1 (TfR1). A Tfr1 gene deletion is lethal in mice with severe anemia and is not compensated by TfR2. 9 In contrast, TfR2 expression is tissue-restricted with high expression in the liver 10 where it plays a key role in iron metabolism regulation. Indeed, TfR2 contributes to the adaptation of hepcidin production to the needs of the body by sensing the circulating iron bound to transferrin. 11 Familial inactivating or non-sense mutations in the TfR2 gene are responsible for...
The early-response gene product IEX-1 (also known as IER3) was recently found to interact with the anti-apoptotic Bcl-2 family member, myeloid cell leukemia-1 (Mcl-1). In this study we show that this interaction specifically and timely controls the accumulation of Mcl-1 in the nucleus in response to DNA damage. The IEX-1 protein is rapidly induced by γ-irradiation, genotoxic agents or replication inhibitors, in a way dependent on ataxia telangiectasia mutated (ATM) activity and is necessary for Mcl-1 nuclear translocation. Conversely, IEX-1 protein proteasomal degradation triggers the return of Mcl-1 to the cytosol. IEX-1 and Mcl-1 are integral components of the DNA damage response. Loss of IEX-1 or Mcl-1 leads to genomic instability and increased sensitivity to genotoxic and replicative stresses. The two proteins cooperate to maintain Chk1 activation and G2 checkpoint arrest. Mcl-1 nuclear translocation may foster checkpoint and improve the tumor resistance to DNA damage-based cancer therapies. Deciphering the pathways involved in IEX-1 degradation should lead to the discovery of new therapeutic targets to increase sensitivity of tumor cells to chemotherapy.
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