ERK involvement in resistance to apoptosis in keratinocytes with mutant keratin.

Abstract

The consequences of cell stress induced by misfolded proteins are an important contributor to many human diseases. One such disease is epidermolysis bullosa simplex (EBS), caused by mutations in the structural proteins (keratins K5 or K14) of the proliferative compartment of the epidermis (basal keratinocyte layer), leading to cell fragility and blistering. In severe EBS, the mutation is associated with aggregates of nonfilamentous keratin protein, and cell lines carrying such mutations show a constitutively activated stress response. Analysis of the cellular mechanisms leading to cell breakdown on physical stress may point the way to mutation-independent therapeutic approaches to these incurable genetic disorders. We therefore subjected EBS cell lines, immortalized from patients with EBS, to an oscillating mechanical stress in assays designed to mimic the physical trauma that leads to cell breakdown in vivo. These experiments show that mechanical stress activates extracellular signal-regulated kinase (ERK) signaling in these cells, and that the keratin mutant cells also show a resistance to apoptosis following mechanical stress that is reversed by inhibiting ERK. The consequences of constitutive expression of large amounts of defective structural protein in a tissue cell must be properly understood for the development of safe and effective therapies for these disorders.

• Authors: David Russell, Heike Ross, E Birgitte Lane
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 130 Issue 3 Pg. 671-81 (Mar 2010) ISSN: 1523-1747 [Electronic] United States
• PMID: 19847192 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 14-3-3 Proteins
• BAD protein, human
• BCL2L1 protein, human
• Blood Proteins
• Butadienes
• Enzyme Inhibitors
• KRT14 protein, human
• KRT5 protein, human
• Keratin-14
• Keratin-5
• Nitriles
• RNA, Small Interfering
• U 0126
• bcl-Associated Death Protein
• bcl-X Protein
• Proto-Oncogene Proteins c-akt
• Cyclic AMP-Dependent Protein Kinases
• Extracellular Signal-Regulated MAP Kinases

Topics

• 14-3-3 Proteins (metabolism)
• Apoptosis (physiology)
• Blood Proteins (pharmacology)
• Butadienes (pharmacology)
• Cell Line, Transformed
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Enzyme Inhibitors (pharmacology)
• Epidermolysis Bullosa Simplex (genetics, metabolism, pathology)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Humans
• Intermediate Filaments (metabolism)
• Keratin-14 (genetics, metabolism)
• Keratin-5 (genetics, metabolism)
• Keratinocytes (cytology, enzymology)
• MAP Kinase Signaling System (physiology)
• Mutagenesis (physiology)
• Nitriles (pharmacology)
• Phosphorylation (physiology)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Small Interfering
• Stress, Mechanical
• bcl-Associated Death Protein (metabolism)
• bcl-X Protein (metabolism)