Disease relevance of Pin1

• Thus, Pin1 is pivotal in protecting against age-dependent neurodegeneration, providing insight into the pathogenesis and treatment of Alzheimer's disease and other tauopathies [1].
• PURPOSE: The peptidyl-prolyl isomrase Pin1 plays a catalytic role in oncogenesis in solid cancers, including prostate cancer [2].
• We show that in human, but not mouse neuroblastoma cells, Pin1 is downregulated in response to ER stress, in accordance with the presence of an ER stress response element in the mouse, but not the human Pin1 gene [3].
• Consistent with earlier findings that Pin1 KO induces tauopathy, here we demonstrate that Pin1 knockdown or KO increased WT tau protein stability in vitro and in mice and that Pin1 overexpression suppressed the tauopathy phenotype in WT tau transgenic mice [4].

Psychiatry related information on Pin1

• Here we show that Pin1 expression is inversely correlated with predicted neuronal vulnerability and actual neurofibrillary degeneration in Alzheimer's disease [1].

High impact information on Pin1

• Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication [5].
• After stimulation by double-stranded RNA, induced phosphorylation of the Ser339-Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3 [5].
• The peptidyl-prolyl isomerase Pin1 binds and stabilizes several phosphorylated transcription and mitosis regulators via its WW interacting domain [6].
• Furthermore, the absence of Pin1 or inhibition of PP2A stabilizes c-Myc [7].
• Analyses using markers of cell cycle parameters and apoptosis revealed that Pin1(-/-) PGCs did not undergo cell cycle arrest or apoptosis [8].

Biological context of Pin1

• We conclude that PGCs have a prolonged cell cycle in the absence of Pin1, which translates into fewer cell divisions and strikingly fewer Pin1(-/-) PGCs by the end of the proliferative phase [8].
• These results indicate that Pin1 regulates the timing of PGC proliferation during mouse embryonic development [8].
• Investigation of the reproductive organs revealed significantly fewer germ cells in the adult Pin1(-/-) testes and ovaries than in wild type or heterozygotes, which resulted from Pin1(-/-) males and females being born with severely reduced number of gonocytes and oocytes [8].
• The cellular changes that result from the loss of Pin1 predispose Pin1 null mouse embryo fibroblasts to undergo more rapid genomic instability when immortalized by conditional inactivation of p53 and sensitizes these cells to more aggressive Ras-dependent transformation and tumorigenesis [9].
• The results show that high PPIase activities of Pin1 are found in organs that have the tendency to develop Pin1 knockout phenotypes and, therefore, provide for the first time an enzymological basis for these observations [10].

Anatomical context of Pin1

• Pin1 regulates the timing of mammalian primordial germ cell proliferation [8].
• Further studies in 8.5 to 13.5 dpc Pin1(-/-) embryos showed that PGCs were allocated properly at the base of the allantois, but their cell expansion was progressively impaired, resulting in a markedly reduced number of PGCs at 13.5 dpc [8].
• Here we show that Pin1 regulates the turnover of cyclin E in mouse embryo fibroblasts [9].
• These results reveal that the presence of Pin1 is required to regulate proliferation and/or cell fate of undifferentiated spermatogonia in the adult mouse testis [11].
• Correspondingly, we show here that Pin1 plays an essential role in maintaining spermatogonia in the adult testis [11].

Other interactions of Pin1

• New data indicate that Pin1 also regulates the function and processing of Tau and APP, respectively, and is important for protecting against age-dependent neurodegeneration [12].
• Furthermore, Pin1 is the only gene known so far that, when deleted in mice, can cause both Tau and Abeta-related pathologies in an age-dependent manner, resembling many aspects of human Alzheimer's disease [12].
• Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1 [5].

Analytical, diagnostic and therapeutic context of Pin1

• Real time PCR experiments of all PPIases in different mouse organs and MEF of Pin1+/+ and Pin1-/- mice support the finding and reveal the specific expression profiles of PPIases in mice [10].

References