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Molecular Biology

, Volume 52, Issue 3, pp 419–429 | Cite as

AICAR-Dependent Activation of AMPK Kinase Is Not Accompanied by G1/S Block in Mouse Embryonic Stem Cells

  • B. B. Grigorash
  • I. I. Suvorova
  • V. A. Pospelov
Molecular Cell Biology

Abstract

Embryonic stem cells (ESCs) have the capacity for self-renewal and pluripotency. Due to high proliferative activity, ESCs use a specific pathway of the formation of ATP molecules, which can lead to the development of the adaptive metabolic response under the conditions of energy deficiency (which is different from the response of differentiated cells). It is known that metabolic signals are integrated with the cell cycle progression; however, the signaling pathways that connect the availability of nutrients with the regulation of cell cycle in ESCs are insufficiently studied. We have studied the effect of the AICAR agent, which imitates an increase in AMP level and induces the activation of the metabolic sensor AMPK, on proliferation, cell cycle distribution, and pluripotency of mouse ESCs (mESCs). It has been demonstrated that cells treated with AICAR do not stop at the control G1/S point of the cell cycle, since they do not accumulate P21/WAF1 (G1/S checkpoint regulator), despite P53 activation. On the contrary, AICAR increases the rate of mESC proliferation, which correlates with increased expression of pluripotency marker genes (OCT3/4, NANOG, SOX2, KLF4, ESRRB, PRDM14). In addition, an increase in the transcription of the HIF1α gene (a key regulator of the cell proliferation and viability, as well as glucose metabolism under stress) was detected. An increase in the expression of glycolytic enzyme genes (LDHA, ALDOA, PCK2, GLUT4) under the effect of AICAR indicates a change in mESC metabolism towards increased glycolysis. Thus, AICAR-dependent AMPK activation as one of possible mechanisms of the mESC adaptive response to the emergence of energetic imbalance is not accompanied by a cell cycle arrest at the G1/S checkpoint, but involves the processes of increasing glycolytic activity.

Keywords

embryonic stem cells AMPK AICAR P53-P21/WAF1 G1/S checkpoint cell cycle differentiation pluripotency metabolism 

Abbreviations

AICAR

5-aminoimidazole-4-carboxamide ribonucleotide

AMPK

AMP-activated protein kinase

LDHA

lactate dehydrogenase A

ALDOA

aldolase A

PCK2

phosphoenolpyruvate carboxykinase 2

GLUT4 and GLUT1

glucose transporter types 4 and 1

RA

retinoic acid

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Copyright information

© Pleiades Publishing, Inc. 2018

Authors and Affiliations

  • B. B. Grigorash
    • 1
  • I. I. Suvorova
    • 1
  • V. A. Pospelov
    • 1
  1. 1.Institute of CytologyRussian Academy of SciencesSt. PetersburgRussia

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