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Changes in Cyclic Adenosine 3':5'-Monophosphate Levels during Induction of Differentiation in Murine Erythroleukemia Cells¹

Departments of Medicine [P. A. M., R. A. R.], Human Genetics and Development [Y. G., R. C. R., P. A. M., R. A. R.], Anatomy [A. D. D.], Pathology [A. D. D.], and the Cancer Center, Columbia University, College of Physicians and Surgeons, New York, New York 10032

Friend virus-infected murine erythroleukemia cells were synchronized with respect to the cell cycle by the sequential exposure to thymidine and hydroxyurea. Upon release from cell cycle arrest, they go through S phase in 5 hr, G₂ and mitosis in 2 hr, and G₁ in 3 hr. Cells exposed to several inducers of erythroid differentiation, hexamethylene bisacetamide, dimethyl sulfoxide, and sodium butyrate, progress through the first synchronized cell cycle with the same kinetics as control cells but remain in the subsequent G₁ for as long as 6 to 8 hr. The cyclic adenosine 3':5'-monophosphate (cAMP) level in synchronized control cells is high at the point of cell cycle arrest by hydroxyurea (G₁-S), falls during S and G₂-M, and then rises again during G₁. In cells cultured with inducers, there is a transient 5- to 6-fold increase in cAMP level during mid-S. Nonsynchronous cultures also display changes in cell cycle kinetics and cAMP levels when exposed to the same inducers. An increased proportion of cells in G₁ can be detected by 8 to 9 hr of exposure to inducer and is recognizable for up to 10 to 20 hr, depending upon the inducer. In nonsynchronized cells a transient increase in cAMP level is observed 2 to 8 hr after addition of inducer. Several cyclic nucleotide phosphodiesterase inhibitors also elevate cAMP content, prolong the G₁ phase, and induce murine erythroleukemia cell differentiation. Two weaker phosphodiesterase inhibitors fail to induce differentiation.

¹ These studies were supported in part by National Cancer Institute Grants CA-18314 and CA-13696, by American Cancer Society Grant CH-68, and by National Science Foundation Grant PCM-75-8696A01). Preliminary results from this work presented at the Cold Spring Harbor Symposium on Differentiation of Normal and Neoplastic Hematopoietic Cells, September 3 to 7, 1977 (24).

² Leukemia Society Scholar.

³ To whom requests for reprints should be addressed, at Cancer Center/ICR, 701 West 168th Street, New York, N. Y. 10032.

Received 5/22/78. Accepted 8/15/78.