P53 protein key to anti-inflammatory action of glucorticoids
MedWire News: Loss of p53, a tumor suppressor protein, impairs repression of nuclear factor (NF)-κB transcription by glucocorticoids, show study findings suggesting that this protein is vital to the anti-inflammatory action of glucocorticoids.
"Steroids are the most potent anti-inflammatories available, but they can cause serious side effects," said lead study author Inder Verma (Salk Institute for Biological Studies, La Jolla, California, USA) in a press release. "We may have found a way to get around these limitations by reducing inflammation without steroids."
The study findings also suggest that cancer patients with a genetic tumor mutation resulting in abnormal p53 activity do not respond to steroid treatment and may be taking these drugs needlessly.
"If p53 is required for glucocorticoids to work, yet their tumor cells aren't producing p53 normally, they may be receiving steroid treatment and dealing with the ramifications with no therapeutic benefit," added Verma. "Maybe we shouldn't give them steroids, or, even better, maybe we can find a new drug that will replace steroids."
To understand the molecular mechanism of repression of NF-κB activity by glucocorticoids, Verma and team performed a high-throughput small interfering RNA (siRNA) oligo screen to identify novel genes involved in the process.
Transduction of human monocytic THP-1 cells with a NF-κB luciferase reporter showed that loss of p53 impaired repression of NF-κB transcription by glucocorticoids. Isolation of bone marrow-derived macrophages from wildtype and p53-knockout mice confirmed these findings.
When the researchers investigated the mechanism of involvement of p53 in suppression of NF-κB activity, they found that loss of p53 impairs transcription of glucocorticoid receptor target genes, whereas upstream NF-κB and glucocorticoid receptor signaling cascades remain intact.
Verma and team then investigated their findings in a mouse model of lipopolysaccharide shock, which showed that glucocorticoid treatment resulted in survival of nine out of 12 wildtype mice compared with three out of 14 p53-knockout mice.
Although the exact mechanisms describing the role of p53 in glucocorticoid receptor repression of NF-κB remains to be discovered, the researchers say that the finding that loss of p53 did not affect glucocorticoid receptor or NF-κB nuclear translocation suggests that p53 aids in glucocorticoid receptor repression of NF-κB when all three proteins are localized to the nucleus.
"Our findings suggest that NF-κB could be upregulated in tumor cells, in part, because endogenous glucocorticoids, due to a loss of p53 function, can no longer efficiently repress NF-κB," write the researchers in the Proceedings of the National Academy of Sciences.
By Ingrid Grasmo