Nutlin-3

The tumor suppressor p53 activates transcription of the IER5 gene, which encodes an adapter protein of protein phosphatase PP2A. IER5 binds to both the B55 regulatory subunit of PP2A and PP2A's target proteins, facilitating PP2A/B55-catalyzed dephosphorylation of these proteins. Here, we show that IER5 functions as a positive regulator of p53 by inhibiting its ubiquitination, thereby increasing cellular p53 levels. Mechanistically, this effect of IER5 requires its nuclear localization and binding to both PP2A/B55 and the p53 ubiquitin E3 ligase MDM2. Importantly, IER5 fails to inhibit p53 ubiquitination in cells treated with the MDM2 inhibitor Nutlin-3. The IER5-PP2A/B55 complex dephosphorylates MDM2 at Ser166, leading to MDM2 ubiquitination and a reduction in nuclear MDM2. Altogether, our data provide evidence that IER5-PP2A/B55 regulates the nuclear balance between MDM2 and p53 via MDM2 dephosphorylation.

Maintaining genomic stability is essential for detecting DNA damage and activating appropriate responses such as repair, apoptosis, or senescence, primarily mediated by the ATM-p53 axis. ATM is the main sensor of double-strand breaks, and once activated, it will either promote the repair of damaged DNA or eliminate the damaged cells through apoptosis. ATM and p53 mutations upset this equilibrium to cause genomic instability, therapy resistance, and tumor progression in the context of cancer. Oncogene-induced senescence is bypassed by ATM inactivation, which allows cells to progress to become tumors, and p53 mutations allow for uncontrolled proliferation and sensitivity to apoptosis. In addition, persistent ATM signaling can trigger a SASP, which paradoxically further enhances an inflammatory tumor microenvironment and contributes to aging-related diseases and cancer progression. Chemical small molecule p53 activators (PRIMA-1, Nutlin-3) and ATM inhibitors (AZD0156, M4076) sensitize cancer to DNA damaging therapy in cells and nude mice without p53. It remains to be seen whether ATM loss results in ATM/p53 signaling that is always detrimental to tumor proliferation or has context-dependent effects since ATM loss can also promote p53-dependent tumor suppression through senescence and apoptosis in specific cancer types. In this review, we consolidate state-of-the-art findings on ATM and p53 coordination in the processes involved in DNA repair, apoptosis, and senescence to show how ATM and p53 dual involvement in tumor suppression and cancer progression is occurring. It also focuses on therapeutic approaches targeting these pathways to benefit from senescence and intimidating cancer treatment outcomes.