Inactivation of the Akt survival pathway during photoreceptor apoptosis in the retinal degeneration mouse.

Abstract

PURPOSE:

Previous work has indicated that the serine-threonine protein kinase Akt is a general mediator of cellular survival signals and that loss of Akt-mediated signaling can lead to the activation of apoptosis. This study was conducted to establish whether regulation of the Akt survival pathway mechanisms is implicated in the induction of apoptosis during photoreceptor cell death in the rd mouse model of retinal degeneration.

METHODS:

Quantitative Western blot analysis and immunocytochemistry were used to examine the activation status and localization of key components of the Akt signaling cascade (Akt, BAD, Forkhead [FKHR], HSP27, mitogen-activated protein (MAP) kinase kinase-3 and -6 (MKK3/6), the tumor-suppressor phosphatase PTEN, and the cytoplasmic protein-tyrosine kinase cSrc-p60), in the retina of the rd mouse in comparison with the control. The time points examined spanned the period of photoreceptor degeneration.

RESULTS:

In the period up to the peak of photoreceptor apoptosis at postnatal day 15, dysregulation of the survival pathway was identified at several levels, including deactivation of both Akt itself and its downstream transcription factor target Forkhead (FKHR) and activation of the upstream negative regulator PTEN.

CONCLUSIONS:

Taken in conjunction with previous studies, the data support a model in which photoreceptor cell death in the rd mouse is the result of combined inactivation of the Akt survival pathway and the activation of the two major apoptotic pathways.

• Authors: Catherine Jomary, Jason Cullen, Stephen E Jones
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 47 Issue 4 Pg. 1620-9 (Apr 2006) ISSN: 0146-0404 [Print] United States
• PMID: 16565401 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bad protein, mouse
• Forkhead Box Protein O1
• Forkhead Transcription Factors
• Foxo1 protein, mouse
• HSP27 Heat-Shock Proteins
• Heat-Shock Proteins
• Hspb2 protein, mouse
• bcl-Associated Death Protein
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins pp60(c-src)
• Proto-Oncogene Proteins c-akt
• MAP Kinase Kinase 3
• MAP Kinase Kinase 6
• Map2k3 protein, mouse
• Map2k6 protein, mouse
• PTEN Phosphohydrolase
• Pten protein, mouse

Topics

• Animals
• Apoptosis
• Blotting, Western
• Cell Survival (physiology)
• Fluorescent Antibody Technique, Indirect
• Forkhead Box Protein O1
• Forkhead Transcription Factors (metabolism)
• HSP27 Heat-Shock Proteins
• Heat-Shock Proteins (metabolism)
• MAP Kinase Kinase 3 (metabolism)
• MAP Kinase Kinase 6 (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• PTEN Phosphohydrolase (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Photoreceptor Cells, Vertebrate (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins pp60(c-src) (metabolism)
• Retinal Degeneration (metabolism)
• Signal Transduction
• bcl-Associated Death Protein (metabolism)