Disease relevance of PIN1

• Reintroducing a recombinant adenovirus encoding Pin1 into Pin1(-/-) MEF cells restores the expression of cyclin D1 and RB phosphorylation [1].
• We have previously reported that Pin1 is overexpressed in oral squamous cell carcinoma (OSCC) and its level correlates with Cyclin D1 expression [2].
• We report that Pin1 mRNA correlates with Cyclin D1 mRNA expression and the expression of many cyclin genes is associated with lymph node metastasis in OSCC [2].
• Furthermore, beta-catenin levels are decreased in Pin1-deficient mice but are increased and correlated with Pin1 overexpression in human breast cancer [3].
• The results show that neoplastic prostate tissues and high-grade intraepithelial prostatic neoplasias (PIN2_3) exhibit a significantly higher number of PNA acceptors than benign prostatic hyperplasias and low (PIN1) grade prostatic intraepithelial neoplasias [4].

Psychiatry related information on PIN1

• Here we show that Pin1 binds to only one pT-P motif in tau and copurifies with PHFs, resulting in depletion of soluble Pin1 in the brains of Alzheimer's disease patients [5].
• Here, Pin1 distribution in AD, and its colocalization with pThr231 tau in AD, FTDP-17 (P301L), Pick's disease (PiD), and PSP was investigated using TG-3, a monoclonal antibody to conformationally altered pThr231 tau [6].

High impact information on PIN1

• Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent [7].
• This raises the possibility of phosphorylation-mediated control of Pin1-substrate interactions in cell cycle regulation [7].
• Pin1 displays a preference for an acidic residue N-terminal to the isomerized proline bond due to interaction of this acidic side chain with a basic cluster [7].
• Here we report that DNA damage specifically induces p53 phosphorylation on Ser/Thr-Pro motifs, which facilitates its interaction with Pin1, a member of peptidyl-prolyl isomerase [8].
• Consequently, Pin1 stimulates the DNA-binding activity and transactivation function of p53 [8].

Chemical compound and disease context of PIN1

• Depletion of Pin1 in MCF-7 human breast cancer cells reduces the endogenous estrogen-dependent recruitment of p300 to the promoters of estrogen receptor-dependent genes [9].

Biological context of PIN1

• The WW domain of the human PIN1 and p13(SUC1), a subunit of the cyclin-dependent kinase complex, were previously shown to be involved in the regulation of the cyclin-dependent kinase complex activity at the entry into mitosis, by an unresolved molecular mechanism [10].
• Since the PIN1 homologue ESS1 is an essential gene, complementation experiments in yeast were performed [11].
• The role of PIN1 in beta-catenin upregulation in HCC was investigated [12].
• Primers were designed to discriminate between the two transcripts, and PCR on DNA from hamster/human somatic cell hybrids retaining chromosomes 1 or 19 was used to map the human PIN1 gene to chromosome 19, and PIN1L, a closely related gene, to chromosome 1 [13].
• Analysis of human ESTs showed that there are two different but closely related human transcripts, one of which corresponds to PIN1 [13].

Anatomical context of PIN1

• Furthermore, PIN1 is an E2F target gene essential for the Neu/Ras-induced transformation of mammary epithelial cells [14].
• Pin1 knockout mice appear to have relatively normal development yet the Pin1(-/-)mouse embryo fibroblast (MEF) cells are defective in re-entering cell cycle in response to serum stimulation after G0 arrest [1].
• We examined Pin1 mRNA and protein expressions in OSCC cell lines, and analyzed Pin1/cyclins expression by RT-PCR [2].
• Pin1 can restore the ability of phosphorylated tau to bind microtubules and promote microtubule assembly in vitro [5].
• Overexpression of KRMP1 caused COS-7 cells to arrest at G(2)-M, and co-expression of Pin1 reversed this effect, indicating their physiological interaction [15].

Associations of PIN1 with chemical compounds

• No direct interaction between the PIN1 WW domain or its catalytic proline cis/trans-isomerase domain and p13(SUC1) was detected, but our study showed that in vitro the WW domain of the human PIN1 antagonizes the binding of the p13(SUC1) to the CDC25 phosphopeptide, by binding to the same phosphoepitope [10].
• Phosphorylation on a serine or threonine residue preceding proline (Ser/Thr-Pro) is a key regulatory mechanism, and the conformation of certain phosphorylated Ser/Thr-Pro bonds is regulated specifically by the prolyl isomerase Pin1 [3].
• Depletion of Pin1 by small interfering RNA (siRNA) reduces hormone-dependent transcription from both transfected reporters and an endogenous steroid receptor target gene [9].
• Unlike Pin1-type enzymes it lacks the phosphoserine or phosphothreonine binding WW domain [11].
• Similar to human Pin1 and yeast Ess1, it exhibits catalytic activity toward substrates containing (Thr(P)/Ser(P))-Pro peptide bonds and comparable inhibition kinetics with juglone [11].

Physical interactions of PIN1

• Instead, phosphorylated rab4 is in a complex with the peptidyl-prolyl isomerase Pin1 during mitosis, but not during interphase [16].
• Pin1 stabilizes Emi1 during G2 phase by preventing its association with SCF(betatrcp) [17].
• In this report, we found that Pin1 could interact with Nek6, one of the human NIMA-related kinases (Neks) [18].
• We also show that RNA polymerase II large subunit interacts with Pin1 in HeLa cells [19].

Enzymatic interactions of PIN1

• Thus, Pin1 likely acts as a general regulator of mitotic proteins that have been phosphorylated by Cdc2 and other mitotic kinases [20].
• The peptidyl-prolyl isomerase Pin1 interacts with hSpt5 phosphorylated by Cdk9 [21].
• We show here that the peptidyl prolyl cis-trans isomerase Pin1 interacts specifically with the phosphorylated form of NFAT [22].
• The X-ray crystal structure of Pin1 bound to a doubly phosphorylated peptide (Tyr-P.Ser-Pro-Thr-P.Ser-Pro-Ser) representing a heptad repeat of the RNA polymerase II large subunit's C-terminal domain (CTD), reveals the residues involved in the recognition of a single P.Ser side chain, the rings of two prolines, and the backbone of the CTD peptide [23].
• Pin1 binds to the phosphorylated Ser178-Pro motif in the Daxx protein, and Pin1 overexpression results in the rapid degradation of Daxx via the ubiquitin-proteasome pathway [24].

Regulatory relationships of PIN1

• IGF-1 induces Pin1 expression in promoting cell cycle S-phase entry [1].
• Together, our results suggest that KRMP1 is a mitotic target regulated by Pin1 and vice versa [15].
• Thus, Pin1 is up-regulated in human tumors and cooperates with Ras signaling in increasing c-Jun transcriptional activity towards cyclin D1 [25].
• This aberrant response leading to neurofibrillary degeneration may be triggered by the sequential combination of three partners: the complex Cdk5/p25 induces both apoptosis and the "abnormal mitotic Tau phosphorylation". These mitotic epitopes may allow for the nuclear depletion of Pin1 [26].
• p53 Protein is activated by Pin1: and also by Cu-SOD prion-like enzyme [27].

Other interactions of PIN1

• Pin1 is also a critical regulator of the tumor suppressor p53 during DNA damage response [14].
• Following evaluation of the slides, data were also analyzed by combining several of the groups into three categories: (a) benign/PIN1; (b) PIN2/PIN3/PIN cannot rule out cancer; and (c) PIN plus cancer [28].
• Furthermore, we found that Cyclin D1 expression and RB phosphorylation are dramatically decreased in Pin1(-/-) MEF cells [1].
• The induction of Pin1 by IGF-1 is mediated via the phosphatidylinositol 3-kinase as well as the MAP kinase pathways [1].
• However, the analysis of the relationship between Pin1 and other cyclin genes has not been demonstrated in human OSCC [2].

Analytical, diagnostic and therapeutic context of PIN1

• In addition, site-directed mutagenesis indicated that the interaction of Pin1 with p54nrb was mediated by three threonine residues located in the proline-rich carboxy-terminal extremity of the protein [29].
• GST-Pin1 pull-down and immunoprecipitation assay revealed that Pin1 binds phosphorylated Thr668-Pro of C99 [30].
• Enzyme immunoassay of brains of the Pin1-deficient mice revealed that production of Abeta40 and Abeta42 was lower than that of the wild-type mice, indicating that Pin1 promotes Abeta production in the brain [30].
• Immunohistochemical assessment with affinity-purified polyclonal Pin1-specific antibodies was performed on formalin-fixed paraffin sections of tissue microarray composed of 580 radical prostatectomy specimens [31].
• The BEACON gene (also known as UBL5) was identified as differentially expressed between lean and obese Psammomys obesus, a polygenic animal model of obesity, type 2 diabetes, and dyslipidemia [32].

References