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Signaling Induced by Erythropoietin and Stem Cell Factor in UT-7/Epo Cells: Transient versus Sustained Proliferation

Department of Molecular Virology and Host Defense, SmithKline Beecham Pharmaceuticals, Collegeville, Pennsylvania, USA;
^a Present Address: Indiana University School of Medicine, Department of Microbiology and Immunology and the Walther Oncology Center, and the Walther Cancer Institute, Indianapolis, Indiana, USA

Key Words. JAK • MAPK • STAT • Differentiation

Connie L. Erickson-Miller, Ph.D., Department of Molecular Virology and Host Defense, SmithKline Beecham Pharmaceuticals, 1250 South Collegeville Road, Collegeville, Pennsylvania 19406, USA. Telephone: 610-917-6790; Fax: 610-917-4181; e-mail: Connie_L_Erickson-Miller{at}SBPHRD.com

UT-7/Epo cells are human factor-dependent erythroleukemic cells, requiring erythropoietin (Epo) for long-term growth. Stem cell factor (SCF) stimulates proliferation of UT-7/Epo only transiently, for three to five days. An investigation of the signal transduction pathways activated by these cytokines in UT-7/Epo cells may identify those signals specifically required for sustained growth. Proliferation assays demonstrate that SCF generates a substantial growth response in UT-7/Epo cells; however, the cells do not multiply or survive past five to seven days. While Epo induces the activation of JAK2 and STAT5, SCF stimulation shows no activation of JAK2 or STATs 1, 3, or 5. The activation of MAPK (p42/44) by SCF was transient, lasting only 30 min, in contrast to Epo, which stimulated phosphorylation of p42/44 for up to 2 h. The expression of the early response genes c-fos, egr1, and cytokine-inducible SH2 protein (CIS) in response to SCF or Epo stimulation demonstrated that the transient expression of p42/44 correlated with the transient expression of c-fos and egr1. In addition, CIS was activated by Epo but not SCF. These data indicate that EpoR, JAK2, and STAT5 activation are not required for the initiation of proliferation of these erythroid cells, that the transient activation of p42/44 correlates with the transient gene expression of c-fos and egr1, and sustained expression of c-fos and egr1 as seen in UT-7/Epo cells continuously grown in Epo may be necessary for long-term proliferation.

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