Selective regulation ofBcl-XLby a Jak kinase-dependent pathway is bypassed in murine hematopoietic malignancies
Open Access
- 15 August 1998
- journal article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 12 (16) , 2475-2487
- https://doi.org/10.1101/gad.12.16.2475
Abstract
Bcl-2 family proteins are key regulators of apoptosis and function as cell death antagonists (e.g., Bcl-2, Bcl-XL, and Mcl-1) or agonists (e.g., Bax, Bad, and Bak). Here we report that among the Bcl-2 family of proteins tested (Bcl-2, Bcl-XL, Mcl-1, Bax, Bad, and Bak), Bcl-XL was unique in that its protein levels were tightly regulated by hemopoietins in both immortal and primary myeloid progenitors. Investigating signaling pathways utilized by cytokine receptors established that the regulation of Bcl-XL protein levels is mediated by the Jak kinase pathway and is independent of other signaling effectors including STATs, PI-3′ kinase, and Ras. Moreover, we provide the first direct evidence that Bcl-X is altered in cancer, because bcl-X expression was activated selectively by retroviral insertions in murine myeloid and T-cell hemopoietic malignancies. Tumors harboring bcl-X insertions had altered bcl-X RNAs, expressed elevated levels of Bcl-XL protein, and lacked the requirements for cytokines normally essential for cell survival. Finally, overexpression of Bcl-XL effectively protected IL-3-dependent myeloid cells from apoptosis following removal of trophic factors. Therefore, Bcl-XL functions as a key cytokine regulated anti-apoptotic protein in myelopoiesis and contributes to leukemia cell survival.Keywords
This publication has 70 references indexed in Scilit:
- Interleukin-3-Induced Phosphorylation of BAD Through the Protein Kinase AktScience, 1997
- In bone marrow derived Baf-3 cells, inhibition of apoptosis by IL-3 is mediated by two independent pathwaysOncogene, 1997
- Two Signals Are Necessary for Cell Proliferation Induced by a Cytokine Receptor gp130: Involvement of STAT3 in Anti-ApoptosisImmunity, 1996
- Cytokine receptor signallingNature, 1995
- Antiapoptosis potential of bcl-2 oncogene by dephosphorylationBiochemistry and Cell Biology, 1994
- Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell deathCell, 1993
- bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell deathCell, 1993
- JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietinCell, 1993
- Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around Jh on chromosome 14 and near a transcriptional unit on 18Cell, 1985
- Neoplastic transformation of mast cells by Abelson-MuLV: abrogation of IL-3 dependence by a nonautocrine mechanismCell, 1985