RGD Reference Report - Silencing of tuberin enhances photoreceptor survival and function in a preclinical model of retinitis pigmentosa (an american ophthalmological society thesis).

General

Silencing of tuberin enhances photoreceptor survival and function in a preclinical model of retinitis pigmentosa (an american ophthalmological society thesis).
Authors:	Tsang, SH Chan, L Tsai, YT Wu, WH Hsu, CW Yang, J Tosi, J Wert, KJ Davis, RJ Mahajan, VB
Citation:	Tsang SH, etal., Trans Am Ophthalmol Soc. 2014 Jul;112:103-15.
RGD ID:	11570529
Pubmed:	PMID:25646031 (View Abstract at PubMed)
PMCID:	PMC4311672 (View Article at PubMed Central)
PURPOSE: To assess the functional consequences of silencing of tuberin, an inhibitor of the mTOR signaling pathway, in a preclinical model of retinitis pigmentosa (RP) in order to test the hypothesis that insufficient induction of the protein kinase B (PKB)-regulated tuberin/mTOR self-survival pathway initiates apoptosis. METHODS: In an unbiased genome-scale approach, kinase peptide substrate arrays were used to analyze self-survival pathways at the onset of photoreceptor degeneration. The mutant Pde6b(H620Q)/Pde6b(H620Q) at P14 and P18 photoreceptor outer segment (OS) lysates were labeled with P-ATP and hybridized to an array of 1,164 different synthetic peptide substrates. At this stage, OS of Pde6b(H620Q)/Pde6b(H620Q) rods are morphologically normal. In vitro kinase assays and immunohistochemistry were used to validate phosphorylation. Short hairpin RNA (shRNA) gene silencing was used to validate tuberin's role in regulating survival. RESULTS: At the onset of degeneration, 162 peptides were differentially phosphorylated. Protein kinases A, G, C (AGC kinases), and B exhibited increased activity in both peptide array and in vitro kinase assays. Immunohistochemical data confirmed altered phosphorylation patterns for phosphoinositide-dependent kinase-1 (PDK1), ribosomal protein S6 (RPS6), and tuberin. Tuberin gene silencing rescued photoreceptors from degeneration. CONCLUSIONS: Phosphorylation of tuberin and RPS6 is due to the upregulated activity of PKB. PKB/tuberin cell growth/survival signaling is activated before the onset of degeneration. Substrates of the AGC kinases in the PKB/tuberin pathway are phosphorylated to promote cell survival. Knockdown of tuberin, the inhibitor of the mTOR pathway, increased photoreceptor survival and function in a preclinical model of RP.

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
retinitis pigmentosa	treatment	ISO	Acan (Mus musculus)	11570529; 11570529		RGD
retinitis pigmentosa	treatment	IMP		11570529		RGD

Objects Annotated

Genes (Rattus norvegicus)

Acan (aggrecan)

Genes (Mus musculus)

Acan (aggrecan)

Genes (Homo sapiens)

ACAN (aggrecan)

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Silencing of tuberin enhances photoreceptor survival and function in a preclinical model of retinitis pigmentosa (an american ophthalmological society thesis).