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A function of p21 during promyelocytic leukemia cell differentiation independent of CDK inhibition and cell cycle arrest

Oncogene volume 18, pages 3235–3243 (1999)Cite this article

Abstract

Retinoic Acid (RA) treatment induces disease remission of Acute Promyelocytic Leukemias (APL) by triggering differentiation of neoplastic cells. Differentiation is mediated by the APL-specific transforming protein PML/RARα and involves its activity as ligand-dependent enhancer factor on RA-target genes. We report here the identification of p21 as a transcriptional target of PML/RARα during RA-induced differentiation of APL cells. We found that RA-treated APL cells undergo two rounds of cell division before entering post mitotic G1, that progression through the G1-S is indispensable for differentiation and coincides with the duration of commitment. RA-treatment induced two peaks of p21 synthesis: early (from the 2nd to the 6th hour), dependent on PML/RARα expression and associated with G1-S transition and high CDK activity; late (from 3rd to the 4th day), independent from PML/RARα and associated with G1 block and low CDK activity. Increased p21 in PML/RARα cells during G1-S had no effect on the cell cycle while an antisense p21 prevented RA-induced differentiation without altering G1-S transition and the late G1 block. These results demonstrate that p21 is an effector of the activity of PML/RARα on differentiation and suggest that p21 exerts a function in G1-S connected to differentiation-commitment and uncoupled from cell cycle and CDK inhibition.

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Acknowledgements

We thank C Matteucci for excellent technical assistance, H Müller for his generous help with the elutriator and G Draetta, K Helin, PP di Fiore, S Minucci and H Müller for many helpful discussions and critical reading of the manuscript. We are also grateful to C Mercurio and M Pearson for hints and suggestions on experiments. M Lafage-Pochitaloff kindly provided the APL blasts and the CP74 α-p21 antibody was a gift from E Harlow. This work was supported by grants from AIRC and EC (Biomed II programme).

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  1. Department of Experimental Oncology, European Institute of Oncology, Milan, 20141, Italy

    Tullia Casini & Pier Giuseppe Pelicci

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  1. Tullia Casini
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  2. Pier Giuseppe Pelicci
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Casini, T., Pelicci, P. A function of p21 during promyelocytic leukemia cell differentiation independent of CDK inhibition and cell cycle arrest. Oncogene 18, 3235–3243 (1999). https://doi.org/10.1038/sj.onc.1202630

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