K562 cells resistant to phorbol 12-myristate 13-acetate-induced growth arrest: dissociation of mitogen-activated protein kinase activation and Egr-1 expression from megakaryocyte differentiation.
The K562 cell line undergoes megakaryocytic differentiation in response to phorbol 12-myristate 13-acetate (PMA) stimulation. This event correlates with mitogen-activated protein kinase activation, cell cycle arrest, and expression of the Egr-1 transcription factor. We have isolated K562 cells that are resistant to the growth-inhibitory action of PMA. Molecular characterization demonstrates that PMA resistance is downstream from PMA-induced activation of the mitogen-activated protein kinase pathway. Although the levels of Egr-1 expression and cyclic AMP-responsive element-binding protein phosphorylation are comparable in wild-type and PMA-resistant clones in response to PMA, the expression of megakaryocytic cell surface marker CD41 is detected only in the wild-type cells. The lack of differentiation of the PMA-resistant clones correlates with a failure of the PMA-treated cells to induce dephosphorylation and down-regulation of the retinoblastoma protein. These cells may provide a useful model system to distinguish those events that are connected to cell cycle arrest from those involved in the differentiation program initiated by PMA.
Shelly
C
C
Department of Cell Biology, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Petruzzelli
L
L
Herrera
R
R
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D051766:Early Growth Response Protein 1; D006801:Humans; D017874:Immediate-Early Proteins; D020014:K562 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D007947:Leukemia, Megakaryoblastic, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014157:Transcription Factors / Q000187:drug effects* / Q000378:metabolism
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate