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A deacetylase-deficient SIRT1 variant opposes full-length SIRT1 in regulating tumor suppressor p53 and governs expression of cancer-related genes.


ABSTRACT: SIRT1 is an NAD-dependent deacetylase and epigenetic regulator essential for normal mammalian development and homeostasis. Here we describe a human SIRT1 splice variant, designated SIRT1-?2/9, in which the deacetylase coding sequence is lost due to splicing between exons 2 and 9. This work aimed to determine if SIRT1-?2/9 is a novel functional product of the SIRT1 gene. Endogenous SIRT1-?2/9 protein was identified in human cell lysate by immunoblotting and splice variant-specific RNA interference (RNAi). SIRT1-?2/9 mRNA is bound by CUGBP2, which downregulates its translation. Using pulldown assays, we demonstrate that SIRT1-?2/9 binds p53 protein. SIRT1-?2/9 maintains basal p53 protein levels and supports p53 function in response to DNA damage, as evidenced by RNAi-mediated depletion of SIRT1-?2/9 prior to damage. In turn, basal p53 downregulates SIRT1-?2/9 RNA levels, while stress-activated p53 eliminates SIRT1-?2/9. Loss of wild-type (wt) p53 has been correlated with overexpression of SIRT1-?2/9 in a range of human cancers. Exogenous SIRT1-?2/9 protein associates with specific promoters in chromatin and can regulate cancer-related gene expression, as evidenced by chromatin immunoprecipitation analysis and RNAi/genomic array data. SIRT1 is of major therapeutic importance, and potential therapeutic drugs are screened against SIRT1 deacetylase activity. Our discovery of SIRT1-?2/9 identifies a new, deacetylase-independent therapeutic target for SIRT1-related diseases, including cancer.

SUBMITTER: Shah ZH 

PROVIDER: S-EPMC3266595 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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A deacetylase-deficient SIRT1 variant opposes full-length SIRT1 in regulating tumor suppressor p53 and governs expression of cancer-related genes.

Shah Zahid H ZH   Ahmed Shafiq U SU   Ford Jack R JR   Allison Simon J SJ   Knight John R P JR   Milner Jo J  

Molecular and cellular biology 20111128 3


SIRT1 is an NAD-dependent deacetylase and epigenetic regulator essential for normal mammalian development and homeostasis. Here we describe a human SIRT1 splice variant, designated SIRT1-Δ2/9, in which the deacetylase coding sequence is lost due to splicing between exons 2 and 9. This work aimed to determine if SIRT1-Δ2/9 is a novel functional product of the SIRT1 gene. Endogenous SIRT1-Δ2/9 protein was identified in human cell lysate by immunoblotting and splice variant-specific RNA interferenc  ...[more]

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