Related Experiment Videos
C/EBPβ LIP augments cell death by inducing osteoglycin
Rina Wassermann-Dozorets1, Menachem Rubinstein1
1Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.
Cell Death & Disease
|April 7, 2017
Summary
Tumor cells lacking osteoglycin (Ogn) show reduced stress-induced death. The transcription factor C/EBPβ
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Osteoglycin (Ogn), an extracellular matrix proteoglycan, is often absent in tumor cells, yet its function in tumor biology remains understudied.
- The transcription factor CCAAT-enhancer-binding protein beta (C/EBPβ) exists in two forms: full-length active (LAP) and truncated dominant-negative (LIP).
- The ratio of LIP to LAP (LIP/LAP) is linked to stress-induced cell death, with drug-resistant cells lacking LIP.
Purpose of the Study:
- To investigate the role of osteoglycin (Ogn) in tumor cell response to stress.
- To elucidate the regulatory mechanism of Ogn expression by C/EBPβ isoforms.
- To determine the impact of the C/EBPβ LIP/LAP ratio on tumor cell resistance to stress.
Main Methods:
- RNA interference (RNAi) to reduce Ogn expression.
- Overexpression of Ogn to study its effects.
- Analysis of C/EBPβ (LAP and LIP isoforms) expression and its correlation with Ogn levels.
- Investigation of the mitogen-activated protein kinase/activator protein 1 (MAPK/AP-1) pathway.
Main Results:
- RNAi-mediated knockdown of Ogn attenuated stress-induced tumor cell death, while Ogn overexpression increased it.
- The transcription factor C/EBPβ was identified as a regulator of Ogn expression.
- A higher LIP/LAP ratio of C/EBPβ correlated positively with increased cell death under stress.
- Elevated LIP/LAP ratio robustly increased Ogn expression and stress-induced cell death via modulation of the MAPK/AP-1 pathway.
- Restoring LIP in drug-resistant tumor cells abolished their resistance to chemotherapy and endoplasmic reticulum (ER) stress.
Conclusions:
- LIP deficiency in tumor cells confers resistance to endoplasmic reticulum (ER) stress by inhibiting Ogn induction.
- Ogn expression and subsequent stress-induced cell death are regulated by the C/EBPβ LIP/LAP ratio.
- Targeting Ogn or modulating C/EBPβ isoforms may represent novel therapeutic strategies for overcoming tumor cell resistance to stress and chemotherapy.