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

Oncogene. 1999 May 27;18(21):3235-43. doi: 10.1038/sj.onc.1202630.


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/RAR alpha 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/RAR alpha 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/RAR alpha expression and associated with G1-S transition and high CDK activity; late (from 3rd to the 4th day), independent from PML/RAR alpha and associated with G1 block and low CDK activity. Increased p21 in PML/RAR alpha 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/RAR alpha on differentiation and suggest that p21 exerts a function in G1-S connected to differentiation-commitment and uncoupled from cell cycle and CDK inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CDC2-CDC28 Kinases*
  • Cell Cycle
  • Cell Differentiation
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinases / metabolism*
  • Cyclins / biosynthesis*
  • Cyclins / genetics
  • G1 Phase
  • Humans
  • Leukemia, Promyelocytic, Acute / physiopathology*
  • Neoplasm Proteins / metabolism*
  • Oncogene Proteins, Fusion / metabolism*
  • Protein Serine-Threonine Kinases / metabolism*
  • S Phase
  • Tretinoin / metabolism
  • Tretinoin / pharmacology
  • Tumor Cells, Cultured
  • U937 Cells
  • Up-Regulation


  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
  • Tretinoin
  • Protein Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases