Journal Article

Activation of p53 by nutlin leads to rapid differentiation of human embryonic stem cells

Maimets, T, Neganova, I, Lako, M, Armstrong, L

2008

Overview

p53 is an important regulator of normal cell response to stress and frequently mutated in human tumours. Here, we studied the effects of activation of p53 and its target gene p21 in human embryonic stem cells. We show that activation of p53 with small-molecule activator nutlin leads to rapid differentiation of stem cells evidenced by changes in cell morphology and adhesion, expression of cell-specific markers for primitive endoderm and trophectoderm lineages and loss of pluripotency markers. p21 is quickly and dose-dependently activated by nutlin. It can also be activated independently from p53 by sodium butyrate, which leads to the differentiation events very similar to the ones induced by p53. During differentiation, the activating phosphorylation site of CDK2 Thr-160 becomes dephosphorylated and cyclins A and E become degraded. The target for CDK2 kinase in p53 molecule, Ser-315, also becomes dephosphorylated. We conclude that the main mechanism responsible for differentiation of human stem cells by p53 is abolition of S-phase entry and subsequent stop of cell cycle in G0/G1 phase accompanied by p21 activation.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Apoptosis / Biological and medical sciences / Blotting, Western / Butyrates - pharmacology / Cancer / Care and treatment / Cell activation / Cell adhesion & migration / Cell Biology / Cell cycle / Cell cycle, cell proliferation / Cell differentiation / Cell Differentiation - drug effects / Cell physiology / Cell Proliferation / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Cells, Cultured / Cyclin A - physiology / Cyclin E - physiology / Cyclin-dependent kinase 2 / Cyclin-Dependent Kinase 2 - genetics / Cyclin-Dependent Kinase 2 - metabolism / Cyclin-dependent kinase inhibitor p21 / Cyclin-Dependent Kinase Inhibitor p21 - genetics / Cyclin-Dependent Kinase Inhibitor p21 - metabolism / Cyclins / Cytology / Embryo cells / Embryonic Stem Cells - drug effects / Embryonic Stem Cells - metabolism / Endoderm / Fibroblasts - cytology / Fundamental and applied biological sciences. Psychology / G1 phase / G1 Phase - physiology / Genetic aspects / Genetics / Health aspects / Human Genetics / Humans / Imidazoles - pharmacology / Internal Medicine / Kinases / Medicine / Medicine & Public Health / Methods / Molecular and cellular biology / Octamer Transcription Factor-3 - genetics / Octamer Transcription Factor-3 - metabolism / Oncology / original-article / p53 Protein / Phosphorylation / Physiological aspects / Piperazines - pharmacology / Pluripotency / Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors / Proto-Oncogene Proteins c-mdm2 - genetics / Proto-Oncogene Proteins c-mdm2 - metabolism / Resting Phase, Cell Cycle - physiology / Reverse Transcriptase Polymerase Chain Reaction / RNA, Messenger - genetics / RNA, Messenger - metabolism / RNA, Small Interfering - pharmacology / Sodium butyrate / Stem cells / Stereoisomerism / Transfection / Trophectoderm / Tumor suppressor genes / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Tumors