Several types of signalosome have been ununcovered in the past twenty years about intracellular signaling; and many more will be surely discovered in the future. P53 ina famous tumor suppressor that intereacts with tens of proteins either inside and outside the nucleus. It is used as a scaffold to recruit dozens of proteins involved in DNA repair, cellular differentiationa and programmed cell death (apoptosis). P53 is also regulated by small molecules like nucleosides (UMP and UTP) and thiamine (vitamin B1 in its active form TPP). A class of molecules involved in celllular signaling are phoshoinositides (PIPs), wihich encompass soluble and lipidic derivatived that work by regulating either enzymes and components of signaling transduction. Now scientist realized about a previously unappreciated nuclear signaling hub: the PIPs-p53 signalosome.
Very recently scientists took stock about its potential roles in cellular homeostasis. This complex not only modulates AKT activation within the nucleus but also integrates two major oncogenic pathways – i.e. p53 dysregulation and PI3K-AKT amplification – into a unified mechanism driving cancer cell migration and invasion. For example, nuclear PIPs signaling expands beyond classical models: phosphoinositides, long thought to be confined to plasma and endomembranes for cytoplasmic signaling, are now shown to form active signaling complexes in the nucleus, reshaping the understanding of lipid-mediated regulation. There are data published in the ’90 that inositol-1,4-diphosphate (1,4-IP2) can directly bind DNA polmerase alpha to regulate the efficieny of DNA strand replication.
Wild-type and mutant p53 serve as nuclear scaffolds: both forms of p53 anchor nuclear PIPns and facilitate the assembly of lipid-protein complexes (signalosomes), directly influencing gene expression, chromatin remodeling and cytoskeletal dynamics. Mutant p53, of course, reshape these dinamics to enhance cancerous growth and evade apoptosis. According to this view, de novo c-Akt activation in the nucleus may happen like in lipid rafts of the plasma membrane. Unlike canonical membrane-bound activation of the PI3K-PDK1-Akt complex, nuclear c-Akt is activated by PI(3,4,5)P₃ generated by the PIPn-p53 complex. This activation promotes cancer cell survival and migration-particularly under stress.
The stability of p53 is regulated by its interaction with the oncoprotein MDM2, a ubiquitin E3 ligase. Recently, nuclear PIPs were reported to bind and stabilize p53. Scientists now report that genotoxic stress induces the type I phosphatidylinositol phosphate kinase (PIPKIα) and its product phosphatidylinositol 4,5-bisphosphate (PIP2) to bind and regulate the stability and function of MDM2. Following genotoxic stress, nuclear PIPKIα interacts to MDM2 to the binding of of MDM2 with PIP2. PIP2 binding to MDM2 differentially regulates the recruitment of the small heat shock proteins αB-crystallin (αBC) and HSP27 to the MDM2-PIP2 complex, acting as an on-off switch that regulates MDM2 stability, ubiquitination activity and interaction with p53. In addition, this pathway is dependent on a source of nuclear phosphoinositide about which scientists have small informations.
However, now they report that a subset of PI transfer proteins (PITPs), which transport PI between membranes to enable membrane-localized PIPs synthesis, also interact with p53 in the nucleus upon genotoxic stress. Class I PITPs (PITPα/β) specifically supply the PI required for the generation of p53-PIPs complexes and subsequent signaling in the nucleus. Additionally, the PI 4-kinase PI4KIIα binds to p53 and the PITPs to catalyze the formation of p53-PI4P. All these informations have therapeutic implications: disruption of the nuclear PIPn-p53 signalosome, especially in mutant p53-driven cancers, could impair metastasis. Targeting nuclear-specific PIPn enzymes or restoring p53 function may synergize with clinically relevant PI3K/Akt inhibitors to suppress cancer dissemination.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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