Differentiation inducers modulate cytokine signaling pathways in a murine erythroleukemia cell line.

Abstract

Hexamethylenebisacetamide (HMBA) is a potent differentiation inducer of murine erythroleukemia cells. Immunoprecipitation followed by Western blotting with an anti-phosphotyrosine (P-Tyr) antibody revealed that HMBA increased P-Tyr levels and/or amounts of several proteins containing P-Tyr in F5-5, a murine erythroleukemia cell line. Among these proteins, we identified a Mr 130,000 protein to be Janus-activated kinase 2 (JAK2). HMBA induced tyrosine phosphorylation of JAK2 and signal transducers and activators of transcription 5 (STAT5) but not other JAKs or STATs. This phosphorylation was apparent 12 h after treatment, maximal at 24 h, and persisted for at least 96 h. Consistently, HMBA increased STAT5 DNA-binding activities. Other chemical inducers, DMSO and butyrate, also induced a sustained activation of JAK2/STAT5, whereas fetal calf serum and erythropoietin induced transient activation but not differentiation. Furthermore, overexpression of a dominant-negative form of STAT5 inhibited the chemically induced differentiation. These results suggest that persistent activation of the signaling pathway plays a significant role in the inducer-mediated differentiation. Our data also suggest that molecular mechanisms for the inducer-mediated activation of JAK2 are independent of cytokine receptor-mediated activation mechanisms. We tentatively conclude that cytokine signaling is an important target of chemical inducers in these cells.

• Authors: T Yamashita, H Wakao, A Miyajima, S Asano
• Journal: Cancer research (Cancer Res) Vol. 58 Issue 3 Pg. 556-61 (Feb 01 1998) ISSN: 0008-5472 [Print] United States
• PMID: 9458105 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetamides
• Antineoplastic Agents
• Cytokines
• DNA, Neoplasm
• DNA-Binding Proteins
• Milk Proteins
• Neoplasm Proteins
• Proto-Oncogene Proteins
• STAT5 Transcription Factor
• Trans-Activators
• Erythropoietin
• Protein-Tyrosine Kinases
• Jak2 protein, mouse
• Janus Kinase 2
• hexamethylene bisacetamide

Topics

• Acetamides (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Cattle
• Cell Differentiation (drug effects)
• Cytokines (physiology)
• DNA, Neoplasm (metabolism)
• DNA-Binding Proteins (metabolism)
• Erythropoietin (pharmacology)
• Fetal Blood
• Friend murine leukemia virus
• Janus Kinase 2
• Leukemia, Erythroblastic, Acute (genetics, pathology)
• Mice
• Milk Proteins
• Neoplasm Proteins (metabolism)
• Phosphorylation
• Protein Processing, Post-Translational (drug effects)
• Protein-Tyrosine Kinases (metabolism)
• Proto-Oncogene Proteins
• STAT5 Transcription Factor
• Signal Transduction (drug effects)
• Trans-Activators (metabolism)
• Tumor Cells, Cultured