Siva1 inhibits p53 function by acting as an ARF E3 ubiquitin ligase

Abstract

The tumour suppressor alternative reading frame (ARF) is one of the most frequently mutated proteins in human cancer. It has been well established that ARF is able to stabilize and activate p53 by directly inhibiting Mdm2. ARF-mediated p53 activation in response to oncogenic stress is thought to be an important determinant of protection against cancer. However, little is known regarding the control of ARF in cells. Here, we show that Siva1 is a specific E3 ubiquitin ligase of ARF. Siva1 physically interacts with ARF both in vitro and in vivo. Through direct interaction, Siva1 promotes the ubiquitination and degradation of ARF, which in turn affects the stability of p53. Functionally, Siva1 regulates cell cycle progression and cell proliferation in an ARF/p53-dependent manner. Our results uncover a novel regulatory mechanism for the control of ARF stability, thereby revealing an important function of Siva1 in the regulation of the ARF-Mdm2-p53 pathway.

Preliminary Research on the Expression, Purification and Function of the Apoptotic Fusion Protein, Sival

“…Functionally, Siva1 regulates cell cycle progression and cell proliferation in an ARF/p53-dependent manner. found that, via the inhibition of stathmin, Siva1 enhances the formation of microtubules and impedes focal adhesion assembly, cell migration, and EMT (Wang et al, 2013). In mouse models, knockdown of Siva1 promotes cancer dissemination, whereas overexpression of Siva1 inhibits it.…”

“…We found that Siva1 can significantly inhibit the migration and invasion of HCT116 cells. Regarding the mechanism underlying the inhibition, (Wang et al, 2013) repored that Siva1 is a specific E3 ubiquitin ligase of tumour suppressor alternative reading frame (ARF) which is one of the most frequently mutated proteins in human cancer. Siva1 promotes the ubiquitination and degradation of ARF, which in turn affects the stability of p53.…”

SIVA, a target of p53, is downregulated in myelodysplastic syndromes

“…SIVA1 binds to and regulates p53 stability by acting as an adapter protein between p53 and MDM2 [29,30], and SIVA1 acts as an ubiquitin ligase for ARF and indirectly regulates p53 stability [31]. Given that there is a reduced expression of SIVA1 in bone marrow samples from MDS, herein identified, further studies are necessary to verify whether SIVA1 downregulation may be involved in aberrant p53 signaling pathway reported in MDS cells [32].…”

SIVA1 (SIVA1, Apoptosis-Inducing Factor)

“…SIVA1 binds to and regulates p53 stability by acting as an adapter protein between p53 and MDM2, and participates in an auto-regulatory feedback loop between p53 and SIVA1 (Du et al, 2009;Mei and Wu, 2012). SIVA1 associates with ARF, enabling its ubiquitination and degradation; this mechanisms also regulates the p53/MDM2 signaling pathway (Wang et al, 2013). Finally, SIVA1 is a novel adaptor protein that promotes Stathmin 1/CaMKII interaction.…”

“…The protein interaction mapping was performed by GST pull down assays using deletion mutants of SIVA1 and ARF overexpressed in 293 cells. SIVA1 binds to ARF by its N-terminal region and DDHR, while the residue aa 21-64 of ARF is required (Wang et al, 2013).…”