Dynamic regulation of Pin1 expression and function during zebrafish development

Abstract

The prolyl isomerase Pin1 plays a key role in the modulation of proline-directed phosphorylation signaling by inducing local conformational changes in phosphorylated protein substrates. Extensive studies showed different roles for Pin1 in physiological processes and pathological conditions such as cancer and neurodegenerative diseases. However, there are still several unanswered questions regarding its biological role. Notably, despite evidences from cultured cells showing that Pin1 expression and activity may be regulated by different mechanisms, little is known on their relevance in vivo. Using Danio rerio (zebrafish) as a vertebrate model organism we showed that pin1 expression is regulated during embryogenesis to achieve specific mRNA and protein distribution patterns. Moreover, we found different subcellular distribution in particular stages and cell types and we extended the study of Pin1 expression to the adult zebrafish brain. The analysis of Pin1 overexpression showed alterations on zebrafish development and the presence of p53-dependent apoptosis. Collectively, our results suggest that specific mechanisms are operated in different cell types to regulate Pin1 function.

Melatonin ameliorates Aβ42‐induced alteration of βAPP‐processing secretases via the melatonin receptor through the Pin1/GSK3β/NF‐κB pathway in SH‐SY5Y cells

“…Although our present data demonstrated that melatonin modulates both NF‐κB and GSK3β to regulate βAPP‐cleaving secretases, the most intriguing part of this study was the identification of Pin1 as a potential target of melatonin. Pin1 expression is regulated during embryogenesis to achieve specific mRNA and protein distribution patterns . Pin1 changes are perpetual features of aging, tauopathy, and neurodegeneration and could serve as biomarkers of the onset or spread of AD neuropathology.…”

“…The levels of cytosolic Pin1 did not change significantly in the present conditions. Although the subcellular localization of Pin1 is dynamically regulated by specific mechanisms, much advance investigations are required to elucidate the underlying regulations of its localization in both normal and diseased conditions. Moreover, melatonin is also a potent antioxidant and free radical scavenger and might help to prevent oxidative modifications of Pin1 which decrease its activity as observed in AD …”

“…Pin1 expression is regulated during embryogenesis to achieve specific mRNA and protein distribution patterns. 71 Pin1 changes are perpetual features of aging, tauopathy, and neurodegeneration 24,72 and could serve as biomarkers of the onset or spread of AD neuropathology. Overexpressing Pin1 or preventing Pin1 inhibition might be a new approach for preventing Aβ generation and blocking tauopathy.…”

Pin1 Modulation in Physiological Status and Neurodegeneration. Any Contribution to the Pathogenesis of Type 3 Diabetes?

“…On the contrary, AP4 (Activating Enhancer Binding Protein 4), the brain-selective transcription factor [26], down regulates Pin1 transcription, and the proteasome is responsible of the protein degradation following its ubiquitination [4,27]. …”

“…The presence of Pro’s unusual structure lowers the free energy difference and allows these conformational changes [4]. The catalytic activity of PPIases modulates enzyme activity, protein stability and cellular localization by mediating conformational changes of substrates [3,5,6,7,8,9].…”