Phosphorylation of HuR by Chk2 Regulates SIRT1 Expression

Abstract

The RNA binding protein HuR regulates the stability of many target mRNAs. Here, we report that HuR associated with the 3' untranslated region of the mRNA encoding the longevity and stress-response protein SIRT1, stabilized the SIRT1 mRNA, and increased SIRT1 expression levels. Unexpectedly, oxidative stress triggered the dissociation of the [HuR-SIRT1 mRNA] complex, in turn promoting SIRT1 mRNA decay, reducing SIRT1 abundance, and lowering cell survival. The cell cycle checkpoint kinase Chk2 was activated by H(2)O(2), interacted with HuR, and was predicted to phosphorylate HuR at residues S88, S100, and T118. Mutation of these residues revealed a complex pattern of HuR binding, with S100 appearing to be important for [HuR-SIRT1 mRNA] dissociation after H(2)O(2). Our findings demonstrate that HuR regulates SIRT1 expression, underscore functional links between the two stress-response proteins, and implicate Chk2 in these processes.

SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol

“…In cultured cancer cells, SirT1 can inhibit apoptosis but also has an inhibitory effect on proliferation of certain cancer cell types (Fu et al, 2006). Several reports show data consistent with SirT1 having an inhibitory effect (Langley et al, 2002;Ota et al, 2006;Abdelmohsen et al, 2007;van der Veer et al, 2007;Huang et al, 2008), a promoting effect (Chua et al, 2005) or no effect (Michishita et al, 2005;Kamel, Boily and McBurney, unpublished data) on cellular senescence. SirT1 expression can be repressed by HIC1 (Chen et al, 2005b), activated by BRCA1 (Wang et al, 2008b), and both suppressed (in fed cells) and activated (with FoxO3a in starved cells) by p53 (Nemoto et al, 2004), three tumorsuppressor proteins.…”

Sirtuins: critical regulators at the crossroads between cancer and aging

“…Loss of HIC1 and concomitant increase in SIRT1 prolongs lifespan, but facilitates tumor development as less apoptosis is induced in response to DNA damage. SIRT1 expression is also regulated at the posttranscriptional level by HuR (Abdelmohsen et al, 2007). HuR is a ubiquitously expressed mRNA-binding Figure 3 Activation of SIRT1 after stress promotes survival through deacetylation of various substrates.…”

“…protein that binds the 3 0 UTR of SIRT1 to stabilize the SIRT1 transcript (Abdelmohsen et al, 2007). HuR decreases dramatically as cells age and reach senescence (Wang et al, 2001) and this leads to a destabilization of SIRT1 mRNA (Abdelmohsen et al, 2007).…”

“…HuR decreases dramatically as cells age and reach senescence (Wang et al, 2001) and this leads to a destabilization of SIRT1 mRNA (Abdelmohsen et al, 2007). High levels of SIRT1 and HuR contribute to the enhanced survival of rapidly proliferating cells after oxidative damage, as opposed to senescent cells that are more sensitive to oxidative damage (Abdelmohsen et al, 2007).…”

“…HuR decreases dramatically as cells age and reach senescence (Wang et al, 2001) and this leads to a destabilization of SIRT1 mRNA (Abdelmohsen et al, 2007). High levels of SIRT1 and HuR contribute to the enhanced survival of rapidly proliferating cells after oxidative damage, as opposed to senescent cells that are more sensitive to oxidative damage (Abdelmohsen et al, 2007). After oxidative damage, HuR is phosphorylated by Chk2, which promotes dissociation of HuR from SIRT1 mRNA, leading to lower levels of SIRT1 and an enhanced sensitivity to apoptosis induction (Abdelmohsen et al, 2007).…”