ING1 is a candidate tumor suppressor that can stimulate the transcriptional activity of p53 and inhibit cell proliferation. The molecular basis of how ING1 activates p53 function remains unclear. In this work, I demonstrate that ING1b and ING1c could bind and stimulate the transcriptional activity and anti-proliferative functions of p53. ING1 could also bind and stimulate the activity of the p53-related proteins p63α and p73α, albeit weaker than for p53. I found that ING1b stimulated the activity of p53 by increasing the level and stability of the p53 protein. The stabilization and activation of p53 by ING1b could be reversed by MDM2 in a dose-dependent manner. Conversely, the degradation and inhibition of p53 by MDM2 could be reversed by ING1b in a dose-dependent manner. Furthermore, I...[ Read more ]

ING1 is a candidate tumor suppressor that can stimulate the transcriptional activity of p53 and inhibit cell proliferation. The molecular basis of how ING1 activates p53 function remains unclear. In this work, I demonstrate that ING1b and ING1c could bind and stimulate the transcriptional activity and anti-proliferative functions of p53. ING1 could also bind and stimulate the activity of the p53-related proteins p63α and p73α, albeit weaker than for p53. I found that ING1b stimulated the activity of p53 by increasing the level and stability of the p53 protein. The stabilization and activation of p53 by ING1b could be reversed by MDM2 in a dose-dependent manner. Conversely, the degradation and inhibition of p53 by MDM2 could be reversed by ING1b in a dose-dependent manner. Furthermore, I showed that ING1b and MDM2 bound to p53 in a mutually exclusive manner. These data are consistent with the model that ING1b disrupts the interaction between p53 and MDM2, leading to the stabilization and activation of p53 and growth inhibition. These findings ascribe to ING1 the novel function of binding to p53 and disrupting the regulation of p53 by MDM2.