Molecular and Cellular Biochemistry

, Volume 436, Issue 1–2, pp 99–110 | Cite as

Activator protein-1 (AP-1): a bridge between life and death in lung epithelial (A549) cells under hypoxia

  • Seema Yadav
  • Namita Kalra
  • Lilly Ganju
  • Mrinalini Singh


Activator protein-1 (AP-1) transcription factor plays a central role in hypoxia to modulate the expression of genes that decides the fate of the cell. The aim of the present study was to explore the role of AP-1 subunits in lung epithelial (A549) cells under hypoxia. Cell cycle studies by flow cytometry indicated that cell viability was unaffected by the initial hypoxia exposure (0.5% O2 at 37 °C) for 6 and 12 h. However, both transient cell cycle arrest and cell death was detected at 24 and 48 h. Flow cytometry and spectrofluorometry data confirmed the increase in ROS levels. Elevated ROS and calcium levels activated the stress-related MAPK signaling cascade. ERK and JNK were activated in early hypoxic exposure (within 6 h), whereas p38 were activated in 48 h of hypoxia. These subtypes further stimulated the subunits of AP-1 at different times of hypoxia exposure to orchestrate different genes responsible for cell proliferation (6 and 12 h) and apoptosis (24 and 48 h). Our results clearly depict the role of AP-1 heterodimer, i.e., p-c-jun/c-fos, p-c-jun/fosB, junD/c-fos, and junD/fosB in cell proliferation/survival by regulating the expression of Bcl-2 and cyclins (D1 and B1) at 6 h and 12 h of hypoxia, whereas junB/Fra-1 heterodimer have important role in apoptosis by regulating the expression of p53, Bax, and cyclin-dependent kinase inhibitors (p16, p21, p27) at 24 h and 48 h of hypoxia. Also, the cell survival signaling pathway NO-AKT interrupted at 24 h and 48 h of hypoxia indicating cell death. In conclusion, hypoxia for different time points activated different subunits of AP-1 that combined to form different heterodimers. These dimers regulated the expression of genes responsible for cell proliferation and apoptosis. Since, AP-1 plays a role in the decisive phenomenon of the cell to choose between proliferation and apoptosis; thus, its subunits or dimers could be a good therapeutic target for many diseases.


Hypoxia Activator protein-1 (AP-1) Mitogen-activated protein kinase (MAPK) Apoptosis Cell proliferation 





Mitogen-activated protein kinase


Janus N-terminal kinase


Extracellular signal-regulated kinases


Protein kinase B


Reactive oxygen species


Nitric oxide



The authors acknowledge the Defence Research and Development Organization (DRDO), Director, Defence Institute of Physiology and Allied Sciences (DIPAS) and Council of Scientific and Industrial Research, India for providing necessary facilities and funding for this study.

Compliance with ethical standards

Conflict of interest

The author(s) declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Seema Yadav
    • 1
  • Namita Kalra
    • 2
  • Lilly Ganju
    • 1
  • Mrinalini Singh
    • 1
  1. 1.Experimental Biology Division, Defence Institute of Physiology and Allied SciencesDefence Research and Development OrganizationDelhiIndia
  2. 2.Metabolic Cell Signaling Research DivisionINMAS- DRDODelhiIndia

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