Amino Acids

, Volume 41, Issue 1, pp 159–171

Gene expression and integrated stress response in HepG2/C3A cells cultured in amino acid deficient medium

  • Angelos K. Sikalidis
  • Jeong-In Lee
  • Martha H. Stipanuk
Original Article


The integrated stress response (ISR), a defense mechanism cells employ when under stress (e.g., amino acid deprivation), causes suppression of global protein synthesis along with the paradoxical increased expression of a host of proteins that are useful in combating various stresses. Genes that were similarly differentially expressed under conditions of either leucine- or cysteine-depletion were identified. Many of the genes known to contain an amino acid response element and to be induced in response to eIF2α phosphorylation and ATF4 heterodimer binding (ATF3, C/EBPβ, SLC7A1, SLC7A11, and TRIB3), as well as others shown to be induced downstream of eIF2α phosphorylation (C/EBPγ, CARS, SARS, CLCN3, CBX4, and PPP1R15A) were among the upregulated genes. Evidence for the induction of the ISR in these cells also included the increased phosphorylation of eIF2α and increased protein abundance of ATF4, ATF3, and ASNS in cysteine- and leucine-depleted cells. Based on genes highly differentially expressed in both leucine- and cysteine-deficient cells, a list of 67 downregulated and 53 upregulated genes is suggested as likely targets of essential amino acid deprivation in mammalian cells.


Amino acid deprivation Integrated stress response eIF2α ATF4 HepG2/C3A 



Integrated stress response


Amino acid response element


Activating transcription factor 4


General control nonderepressible 2, or eIF2α kinase 4


Open reading frame

Supplementary material

726_2010_571_MOESM1_ESM.pdf (213 kb)
Supplementary material 1 (PDF 212 kb)
726_2010_571_MOESM2_ESM.pdf (234 kb)
Supplementary material 2 (PDF 233 kb)
726_2010_571_MOESM3_ESM.pdf (270 kb)
Supplementary material 3 (PDF 270 kb)
726_2010_571_MOESM4_ESM.pdf (262 kb)
Supplementary material 4 (PDF 262 kb)

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Angelos K. Sikalidis
    • 1
  • Jeong-In Lee
    • 1
  • Martha H. Stipanuk
    • 1
  1. 1.Division of Nutritional SciencesCornell UniversityIthacaUSA

Personalised recommendations