Erythropoietin-dependent Inhibition of Apoptosis Is Supported by Carboxyl-truncated Receptor Forms and Blocked by Dominant-negative Forms of Jak2 (*)

Apoptosis, or programmed cell death (PCD), recently has emerged as an important homeostatic mechanism within several hematopoietic lineages. This process is subject to both positive and negative modulation by cytokines and within the erythroid lineage is inhibited by interleukin-3, stem cell factor, and erythropoietin (Epo). Through the expression of carboxyl-truncated Epo receptor mutants in FDC-P1 cells, a receptor form possessing 80 membrane-proximal cytoplasmic residues is shown to efficiently mediate Epo-dependent inhibition of PCD. This is in contrast to previous studies that attributed this activity to a distal carboxyl-terminal receptor subdomain (and/or heterodimerization of wild type Epo receptors with a truncated non-functional receptor form). Epo-dependent inhibition of PCD also is shown to be blocked by ectopic expression of kinase-deficient dominant-negative forms of Jak2 (Jak2ΔVIII and Jak2-829), further underlining a role of this membrane-proximal subdomain of the Epo receptor in the inhibition of PCD. To our knowledge, this comprises the first direct evidence for an essential role for a Jak tyrosine kinase (Jak2) in this apoptotic response pathway.

[1]  P. G. Tyler,et al.  Interleukin-3 and bryostatin-1 mediate hyperphosphorylation of BCL2 alpha in association with suppression of apoptosis. , 1994, The Journal of biological chemistry.

[2]  T. He,et al.  Dominant negative effects of a carboxy-truncated Jak2 mutant on Epo-induced proliferation and Jak2 activation. , 1994, Biochemical and Biophysical Research Communications - BBRC.

[3]  J. Ihle,et al.  Erythropoietin induces association of the JAK2 protein tyrosine kinase with the erythropoietin receptor in vivo. , 1994, Blood.

[4]  T. He,et al.  Inhibition of erythropoietin-induced mitogenesis by a kinase-deficient form of Jak2. , 1994, The Journal of biological chemistry.

[5]  T. Takizawa,et al.  Differential expression of bcl-2 and susceptibility to anti-Fas-mediated cell death in peripheral blood lymphocytes, monocytes, and neutrophils. , 1994, Blood.

[6]  D. Bergstrom,et al.  Participation of cyclin A in Myc-induced apoptosis. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[7]  T. He,et al.  The extended box 2 subdomain of erythropoietin receptor is nonessential for Jak2 activation yet critical for efficient mitogenesis in FDC-ER cells. , 1994, The Journal of biological chemistry.

[8]  E. Liu,et al.  Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells , 1994, Nature.

[9]  J. Johnston,et al.  Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2 , 1994, Nature.

[10]  B. Hoffman,et al.  Molecular controls of apoptosis: differentiation/growth arrest primary response genes, proto-oncogenes, and tumor suppressor genes as positive & negative modulators. , 1994, Oncogene.

[11]  N. Sato,et al.  JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region , 1994, Molecular and cellular biology.

[12]  H. Ruley,et al.  Apoptosis in erythroid progenitors deprived of erythropoietin occurs during the G1 and S phases of the cell cycle without growth arrest or stabilization of wild-type p53 , 1994, Molecular and cellular biology.

[13]  A. Wilks,et al.  Interferon-gamma induces tyrosine phosphorylation of interferon-gamma receptor and regulated association of protein tyrosine kinases, Jak1 and Jak2, with its receptor. , 1994, The Journal of biological chemistry.

[14]  K. Hirayasu,et al.  Purification of genomic DNA from human whole blood by isopropanol-fractionation with concentrated Nal and SDS. , 1994, Nucleic acids research.

[15]  H. Nakauchi,et al.  A truncated erythropoietin receptor and cell death: a reanalysis. , 1994, Science.

[16]  F. Behm,et al.  Interleukin-4 induces programmed cell death (apoptosis) in cases of high-risk acute lymphoblastic leukemia. , 1994, Blood.

[17]  N. Aoki,et al.  Erythropoietin-dependent association of phosphatidylinositol 3-kinase with tyrosine-phosphorylated erythropoietin receptor. , 1994, The Journal of biological chemistry.

[18]  K. Bhalla,et al.  Effect of combined treatment with interleukin-3 and interleukin-6 on 4-hydroperoxycyclophosphamide-induced programmed cell death or apoptosis in human myeloid leukemia cells , 1993 .

[19]  M. Carroll,et al.  Erythropoietin receptor signals both proliferation and erythroid-specific differentiation. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[20]  M. Erdos,et al.  Tyrosine kinase(s) regulate apoptosis and bcl-2 expression in a growth factor-dependent cell line. , 1993, The Journal of biological chemistry.

[21]  J. Cleveland,et al.  Activation of apoptosis associated with enforced myc expression in myeloid progenitor cells is dominant to the suppression of apoptosis by interleukin-3 or erythropoietin , 1993 .

[22]  K. Muta,et al.  Apoptosis of human erythroid colony‐forming cells is decreased by stem cell factor and insulin‐like growth factor I as well as erythropoietin , 1993, Journal of cellular physiology.

[23]  O. Silvennoinen,et al.  Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase , 1993, Cell.

[24]  O. Silvennoinen,et al.  JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin , 1993, Cell.

[25]  J. Lotem,et al.  Control of programmed cell death in normal and leukemic cells: new implications for therapy. , 1993, Blood.

[26]  P. Walker,et al.  Relationship between apoptosis and the cell cycle in lymphocytes: roles of protein kinase C, tyrosine phosphorylation, and AP1. , 1993, Experimental cell research.

[27]  Richard J Smeyne,et al.  Continuous c-fos expression precedes programmed cell death in vivo , 1993, Nature.

[28]  D. Lane.  A death in the life of p53 , 1993, Nature.

[29]  A. Davies,et al.  The proto-oncogene bcl-2 can selectively rescue neurotrophic factor-dependent neurons from apoptosis , 1993, Cell.

[30]  John Calvin Reed,et al.  Apoptosis induced by withdrawal of interleukin-3 (IL-3) from an IL-3-dependent hematopoietic cell line is associated with repartitioning of intracellular calcium and is blocked by enforced Bcl-2 oncoprotein production. , 1993, The Journal of biological chemistry.

[31]  A. Wyllie,et al.  Apoptosis (the 1992 Frank Rose Memorial Lecture). , 1993, British Journal of Cancer.

[32]  R. Schwall.  A truncated erythropoietin receptor and cell death , 1993, Science.

[33]  J. Louis,et al.  CNTF protection of oligodendrocytes against natural and tumor necrosis factor-induced death , 1993, Science.

[34]  Bruno Amati,et al.  Oncogenic activity of the c-Myc protein requires dimerization with Max , 1993, Cell.

[35]  Cohen Jj.  Glucocorticoid-induced apoptosis in the thymus. , 1992 .

[36]  D. Green,et al.  Apoptotic cell death induced by c-myc is inhibited by bcl-2 , 1992, Nature.

[37]  D. Quelle,et al.  Mutations in the WSAWSE and cytosolic domains of the erythropoietin receptor affect signal transduction and ligand binding and internalization , 1992, Molecular and cellular biology.

[38]  H. Nakauchi,et al.  A Truncated Erythropoietin Receptor That Fails to Prevent Programmed Cell Death of Erythroid Cells , 1992, Science.

[39]  D. Liebermann,et al.  Deregulated c-myb disrupts interleukin-6- or leukemia inhibitory factor-induced myeloid differentiation prior to c-myc: role in leukemogenesis , 1992, Molecular and cellular biology.

[40]  L. Gerschenson,et al.  Apoptosis: a different type of cell death , 1992, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[41]  M. Erdos,et al.  Interleukin (IL)-2 and IL-3 induce distinct but overlapping responses in murine IL-3-dependent 32D cells transduced with human IL-2 receptor beta chain: involvement of tyrosine kinase(s) other than p56lck. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[42]  J. Cleveland,et al.  Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. , 1991, Oncogene.

[43]  Atsushi Hase,et al.  The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis , 1991, Cell.

[44]  D. Quelle,et al.  Localized cytosolic domains of the erythropoietin receptor regulate growth signaling and down-modulate responsiveness to granulocyte-macrophage colony-stimulating factor. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[45]  A. Wilks,et al.  Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase , 1991, Molecular and cellular biology.

[46]  J. Spivak,et al.  Erythropoietin is both a mitogen and a survival factor. , 1991, Blood.

[47]  R. Hawley,et al.  Suppression of programmed death and G1 arrest in B‐cell hybridomas by interleukin‐6 is not accompanied by altered expression of immediate early response genes , 1990, Journal of cellular physiology.

[48]  R. Schreiber,et al.  Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death , 1990, Nature.

[49]  M. Koury,et al.  Control of red cell production: the roles of programmed cell death (apoptosis) and erythropoietin , 1990, Transfusion.

[50]  S. Korsmeyer,et al.  Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. , 1990, Journal of immunology.

[51]  M. Koury,et al.  Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells. , 1990, Science.

[52]  T. Dexter,et al.  Haemopoietic colony stimulating factors promote cell survival by suppressing apoptosis , 1990, Nature.

[53]  M. Koury,et al.  Maintenance by erythropoietin of viability and maturation of murine erythroid precursor cells , 1988, Journal of cellular physiology.

[54]  J. Cohen,et al.  Programmed cell death in the immune system. , 1991, Advances in immunology.