How Does M2 Regulate Ddm2

The activities of MDM2 are highly controlled by extracellular and intracellular stress signals.These signals include genotoxic stress signals, ribosomal stress, oncogenic activation, and psychological stress signals. They function through distinct signalling pathways to regulate the ability of MDM2 to bind with p53, MDM2 E3 ubiquitin ligase activity, and the cellular localization of MDM2. The ability of MDM2 to export p53 to cytoplasm is blocked by the phosphorylation of MDM2 at these two positions. Genotoxic stress signals such as Ionizing radiation (IR) and UV irradiation could cause DNA damage and this activates protein kinases ATM and ATR. ATM and ATR phosphorylate MDM2 at Ser-395 and Ser-407, respectively. The ability of MDM2 to export
p53 to cytoplasm is blocked by the phosphorylation of MDM2 at these two positions. E3 ligase activity of MDM2 is diminished by phosphorylation of MDM2 at Ser-395. This enhances p53 protein synthesis by improving the interaction of MDM2 with p53 mRNA [39].

The following mechanisms describe the indirect regulation of MDM2 by ATM 1) the function of MDM2 to regulate p53 negatively is reduced when ATM activates c-Abl, to phosphorylate MDM2 at multiple sites.
2) ATM reduces the levels of herpes virus associated ubiquitin-specific protease (HAUSP).
HAUSP specifically prevents MDM2 from autoubiquitination.
The reduction in HAUSP levels amplifies MDM2 degradation through auto-ubiquitination [40]. These MDM2 regulations result in an increase of p53 protein levels and activity. Agitations of ribosomal biogenesis induces ribosomal stress and affects the activity of MDM2 and the function of p53. Ribosomal biogenesis is a coordinated cellular process and a key player in several important cellular activities. A number of RPs, including RPL5, RPL11, RPL23, RPL26, RPS3, RPS7, RPS14, and RPS27/L, have been shown to interact with MDM2, by binding mainly to the central region of MDM2. This interaction inhibits the E3 ubiquitin ligase activity of MDM2 by reducing the flexibility of MDM2 protein, leading to the accumulation and activation of p53 [41]. Although, it is obscure why various RPs bind to and control in reponse to ribosomal stress. Oncogenic activation ARF, a tumor suppressor, negatively regulates MDM2 function. The build-up of MDM2 in the nucleoli is stimulated when the central domain of the MDM2 binds to ARF. The E3 ubiquitin ligase activity of MDM2 is also down-regulated by this interaction [39]. Sudies revealed that ARF levels are heightened as a result of abnormal activation of some oncogenes, like E2F-1, beta-catenin, Myc, and Ras. Thus, MDM2 is isolated from p53 and the activity of MDM2 to negatively regulate p53 is reduced; p53 is in turn activated by the down-regulation of MDM2 function which is vital for tumor
suppression. Oftentimes, deletion and silencing of ARF are observed in cancers that disturb the ARF-MDM2-p53 signaling for tumor surveillance [39]. Furthermore, recent results revealed that MDM2 expression can be inhibited by E2F1 can directly inhibit by suppressing its promoter activity in a p53-dependent manner. According to epidemiological studies, the start, advancement, and mortality of human cancers is negatively affected by chronic psychological stress [43]. Results from recent studies show that the neurohormones such as glucocorticoids and catecholamines, which are elevated during chronic stress, can activate MDM2 to down-regulate p53 through distinct pathways. This transcriptionally induces SGK1 kinase, which phosphorylates MDM2 at Ser-166/186, and consequently down-regulates p53 function. Through PKA- b-arrestin pathway, catecholamines, such as epinephrine and norepinephrine, bind to adrenergic receptor (AR), b2-AR, to activate MDM2 [44].
The activation of b-arrestin-1 promotes AKT-mediated activation of MDM2, as well as the interaction of MDM2 with p53. Under chronic stress, neurohormones activate MDM2 to regulate p53 negatively, thereby, promoting could be an important mechanism by which chronic stress promotes tumorigenesis