The p53 tumor suppressor protein selleck chemicals is activated by a var iety of cellular stressors including reactive o ygen species, DNA damage, hypo ia and oncogene stimulation, and assists in the cellular response to stress by regulating cell growth and apoptosis. Post translational modifications, including phosphorylation, modify the activity of p53 by regulating protein stability and enhancing DNA binding and transcriptional activity. Phosphorylation of p53 at serine 15 contributes to stability of p53 by interfering with binding to the E3 ubiquitin ligase, Mdm2, and is also critical for the transactivation activity of p53 by promoting its association with the p300 coactivator protein. Intracellular signaling resulting from DNA damage leads to phosphorylation of p53 at serines 15, 20 and 37 resulting in decreased association with Mdm2, thereby enhancing stability and activity of the p53 protein.
Phosphorylation of serine 15 is critical for p53 induced apoptosis and has been associated with increased e pression of p53 responsive pro apoptotic genes. Oligomerization of p53, which is critical to its transcriptional activity, is regulated by phosphorylation at serine 392. The involvement of ERK in the regulation of p53 stability and activity through direct phosphoryl ation has long been recognized. In the present study, eIF5A1 over e pression induced MEK dependent accumulation and phosphorylation of the p53 tumor suppressor protein on serines 15, 37, and 392, as well as up regulation of the p53 responsive genes, TNFR1 and p53.
However, in spite of increased p53 activity in Ad eIF5A1 infected cells, an inhibitor of p53 was not sufficient to in hibit eIF5A1 induced apoptosis. Thus, apoptosis of A549 lung cancer cells induced by eIF5A1 does not appear to be dependent on p53 activity, although increased e pression stability of p53 induced by eIF5A1 may lower the apoptotic threshold and thereby contribute to the pro apoptotic activity of eIF5A. Increased e pression of Ba and the BH3 only pro tein, Bid, was observed in response to Ad eIF5A1 over e pression, both being pro apoptotic proteins that are transcriptionally regulated by stress activated p53. Hypusine modified eIF5A1 has been proposed to act as a tumor suppressor in Eu myc lymphomagenesis in mice, in part by promoting e pression of Ba .
However, in the present study, increased e pression of both p53 and Ba was correlated with an accumulation of unmodified eIF5A, since hypusine eIF5A1 levels were relatively unaffected by Ad eIF5A1 infection. The pro apoptotic BH3 only AV-951 Bcl 2 family member, Bid, is cleaved by caspase 8 and then interacts with other pro apoptotic Bcl 2 family members, specifically Ba and Bak, to connect activation of the death receptor path way to the internal mitochondrial apoptosis pathway.
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