Biomedical subjects

K P Lu

Publications and source records attributed to K P Lu.

At least 19 recordsLinked to original sources

PubMed2005

Novel genomic targets in oxidant-induced vascular injury.

To study the complex interaction between oxidative injury and the pathogenesis of vascular disease, vascular gene expression was examined in male Sprague-Dawley rats given 35 or 70 mg/kg allylamine, a synthetic amine converted to acrolein and hydrogen peroxide within the vascular wall. Vascular lesions and extensive vascular remodeling, coupled to increased production of 8-epi-PGF2alpha, nuclear localization of NFkappaB, and alterations in glutathione homeostasis, were observed in animals treated with allylamine for up to 20 days. Transcriptional profiling, immunohistochemistry, and in situ hybridization showed that genes involved in adhesion and extracellular matrix (ECM) (alpha(1) integrin, collagen), cytoskeletal rearrangements (alpha-smooth muscle actin, alpha-tropomyosin), and signal transduction (NFkappaB, osteopontin, and LINE) were altered by oxidant treatment. To evaluate mechanisms of gene dysregulation, cultured aortic smooth muscle cells were challenged with allylamine or its metabolites and processed for molecular analysis. These agents increased formation of reactive oxygen species and elicited changes in gene expression similar to those observed in vivo. Oxidative stress and changes in gene expression were inhibited by N-acetyl cysteine, a precursor of glutathione. These results indicate that genes along the ECM-integrin-cytoskeletal axis, in addition to LINE, are molecular targets in oxidant-induced vascular injury.

Acetylcysteine↗

PubMed2003

Genomic profiles and predictive biological networks in oxidant-induced atherogenesis.

Atherogenic stimuli trigger complex responses in vascular smooth muscle cells (VSMCs) that culminate in activation/repression of overlapping signal transduction cascades involving oxidative stress. In the case of benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon present in tobacco smoke, the atherogenic response involves interference with redox homeostasis by oxidative intermediates of BaP metabolism. The present studies were conducted to define genomic profiles and predictive gene biological networks associated with the atherogenic response of murine (aortic) VSMCs to BaP. A combined oxidant-antioxidant treatment regimen was used to identify redox-sensitive targets during the early course of the atherogenic response. Gene expression profiles were defined using cDNA microarrays coupled to analysis of variance and several clustering methodologies. A predictor algorithm was then applied to gain insight into critical gene-gene interactions during atherogenesis. Supervised and nonsupervised analyses identified clones highly regulated by BaP, unaffected by antioxidant, and neutralized by combined chemical treatments. Lymphocyte antigen-6 complex, histocompatibility class I component factors, secreted phosphoprotein, and several interferon-inducible proteins were identified as novel redox-regulated targets of BaP. Predictor analysis confirmed these relationships and identified immune-related genes as critical molecular targets of BaP. Redox-dependent patterns of gene deregulation indicate that oxidative stress plays a prominent role during the early stages of BaP-induced atherogenesis.

Algorithms↗

PubMed2002

Involvement of the telomeric protein Pin2/TRF1 in the regulation of the mitotic spindle.

Pin2/TRF1 was independently identified as a telomeric DNA-binding protein (TRF1) that regulates telomere length, and as a protein (Pin2) that can bind the mitotic kinase NIMA and suppress its lethal phenotype. We have previously demonstrated that Pin2/TRF1 levels are cell cycle-regulated and its overexpression induces mitotic arrest and then apoptosis. This Pin2/TRF1 activity can be potentiated by microtubule-disrupting agents, but suppressed by phosphorylation of Pin2/TRF1 by ATM; this negative regulation is critical in mediating for many, but not all, ATM-dependent phenotypes. Interestingly, Pin2/TRF1 specifically localizes to mitotic spindles in mitotic cells and affects the microtubule polymerization in vitro. These results suggest a role of Pin2/TRF1 in mitosis. However, nothing is known about whether Pin2/TRF1 affects the spindle function in mitotic progression. Here we characterized a new Pin2/TRF1-interacting protein, EB1, that was originally identified in our yeast two-hybrid screen. Pin2/TRF1 bound EB1 both in vitro and in vivo and they also co-localize at the mitotic spindle in cells. Furthermore, EB1 inhibits the ability of Pin2/TRF1 to promote microtubule polymerization in vitro. Given that EB1 is a microtubule plus end-binding protein, these results further confirm a specific interaction between Pin2/TRF1 and the mitotic spindle. More importantly, we have shown that inhibition of Pin2/TRF1 in ataxia-telangiectasia cells is able to fully restore their mitotic spindle defect in response to microtubule disruption, demonstrating for the first time a functional involvement of Pin2/TRF1 in mitotic spindle regulation.

Antineoplastic Agents↗

PubMed2002

Differential expression of ribosomal L31, Zis, gas-5 and mitochondrial mRNAs following oxidant induction of proliferative vascular smooth muscle cell phenotypes.

Treatment of cultured vascular smooth muscle cells (vSMCs) with benzo(a)pyrene (BaP), a prooxidant present in the particulate phase of tobacco smoke, induces highly proliferative (i.e. atherogenic) phenotypes. Critical early target genes in vSMCs have been identified, but patterns of gene expression following repeated cycles of carcinogen treatment in vivo have yet to be evaluated. In the present study, male Sprague-Dawley rats (175-200 g) were given weekly injections of BaP (10 mg/kg) for 8 weeks to induce atherogenic phenotypes. At the end of this atherogenic regimen, vSMCs were established in serial culture and monitored for patterns of proliferative activity and gene expression. vSMCs isolated from BaP-treated animals (hence forth referred to as BaP cells) exhibited constitutively increased growth rates, and marked enhancement of proliferation in response to serum mitogens. Differential display polymerase chain reaction (DD-PCR) and Northern blot analyses revealed that mRNAs for ribosomal protein L31 and Zis genes were suppressed, while gas-5 and mitochondrial mRNAs were overexpressed in BaP cells relative to control mRNA populations. In situ hybridization experiments in vascular tissue confirmed these alterations in vivo. This is the first report linking expression of these genes to proliferative dysregulation during the course of experimentally-induced atherogenesis.

Animals↗

PubMed2001

The Pin2/TRF1-interacting protein PinX1 is a potent telomerase inhibitor.

Telomerase activity is critical for normal and transformed human cells to escape from crisis and is implicated in oncogenesis. Here we describe a novel Pin2/TRF1 binding protein, PinX1 that inhibits telomerase activity and affects tumorigenicity. PinX1 and its small TID domain bind the telomerase catalytic subunit hTERT and potently inhibit its activity. Overexpression of PinX1 or its TID domain inhibits telomerase activity, shortens telomeres, and induces crisis, whereas depletion of endogenous PinX1 increases telomerase activity and elongates telomeres. Depletion of PinX1 also increases tumorigenicity in nude mice, consistent with its chromosome localization at 8p23, a region with frequent loss of heterozygosity in a number of human cancers. Thus, PinX1 is a potent telomerase inhibitor and a putative tumor suppressor.

Amino Acid Sequence↗

PubMed2001

A specific interaction between the telomeric protein Pin2/TRF1 and the mitotic spindle.

Pin2/TRF1 was independently identified as a telomeric DNA binding protein (TRF1) [1] and as a protein (Pin2) that can bind the mitotic kinase NIMA and suppress its ability to induce mitotic catastrophe [2, 3]. Pin2/TRF1 has been shown to bind telomeric DNA as a dimer [3-7] and to negatively regulate telomere length [8-11]. Interestingly, Pin2/TRF1 levels are regulated during the cell cycle, being increased in late G2 and mitosis and degraded as cells exit from mitosis [3]. Furthermore, overexpression of Pin2/TRF1 induces mitotic entry and then apoptosis [12]. This Pin2/TRF1 activity can be significantly potentiated by the microtubule-disrupting agent nocodazole [12] but is suppressed by phosphorylation of Pin2/TRF1 by ATM; this negative regulation is important for preventing apoptosis upon DNA damage [13]. These results suggest a role for Pin2/TRF1 in mitosis. However, nothing is known about how Pin2/TRF1 is involved in mitotic progression. Here, we describe a surprising physical interaction between Pin2/TRF1 and microtubules in a cell cycle-specific manner. Both expressed and endogenous Pin2/TRF1 proteins were localized to the mitotic spindle during mitosis. Furthermore, Pin2/TRF1 directly bound microtubules via its C-terminal domain. Moreover, Pin2/TRF1 also promoted microtubule polymerization in vitro. These results demonstrate for the first time a specific interaction between Pin2/TRF1 and microtubules in a mitosis-specific manner, and they suggest a new role for Pin2/TRF1 in modulating the function of microtubules during mitosis.

Binding Sites↗

PubMed2001

Critical role for the EB1 and APC interaction in the regulation of microtubule polymerization.

Human EB1 was originally cloned as a protein that interacts with the COOH terminus of adenomatous polyposis coli (APC). Interestingly, this interaction is often disrupted in colon cancer, due to mutations in APC. EB1 also interacts with the plus-ends of microtubules and targets APC to microtubule tips. Since APC is detected on the kinetochores of chromosomes, it has been hypothesized that the EB1-APC interaction connects microtubule spindles to the kinetochores and regulates microtubule stability. In yeast, EB1 regulates microtubule dynamics, and its binding domain in APC may be conserved in Kar9, an EB1 binding protein involved in the microtubule-capturing mechanism. These results suggest that the interaction of EB1 and APC is important and may be conserved. However, it is largely unknown whether the EB1-APC interaction affects microtubule dynamics. Here, we show that EB1 potently promotes microtubule polymerization in vitro and in permeabilized cells, but, surprisingly, only in the presence of the COOH-terminal EB1 binding domain of APC (C-APC). Significantly, this C-APC activity is abolished by phosphorylation, which also disrupts its ability to bind to EB1. Furthermore, yeast EB1 protein effectively substitutes for the human protein but also requires C-APC in promoting microtubule polymerization. Finally, C-APC is able to promote microtubule polymerization when stably expressed in APC mutant cells, demonstrating the ability of C-APC to promote microtubule assembly in vivo. Thus, the interaction between EB1 and APC plays an essential role in the regulation of microtubule polymerization, and a similar mechanism may be conserved in yeast.

3T3 Cells↗

PubMed2001

Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1.

Phosphorylation on serines or threonines preceding proline (Ser/Thr-Pro) is a major signaling mechanism. The conformation of a subset of phosphorylated Ser/Thr-Pro motifs is regulated by the prolyl isomerase Pin1. Inhibition of Pin1 induces apoptosis and may also contribute to neuronal death in Alzheimer's disease. However, little is known about the role of Pin1 in cancer or in modulating transcription factor activity. Here we report that Pin1 is strikingly overexpressed in human breast cancers, and that its levels correlate with cyclin D1 levels in tumors. Overexpression of Pin1 increases cellular cyclin D1 protein and activates its promoter. Furthermore, Pin1 binds c-Jun that is phosphorylated on Ser63/73-Pro motifs by activated JNK or oncogenic Ras. Moreover, Pin1 cooperates with either activated Ras or JNK to increase transcriptional activity of c-Jun towards the cyclin D1 promoter. Thus, Pin1 is up-regulated in human tumors and cooperates with Ras signaling in increasing c-Jun transcriptional activity towards cyclin D1. Given the crucial roles of Ras signaling and cyclin D1 overexpression in oncogenesis, our results suggest that overexpression of Pin1 may promote tumor growth.

Adult↗

PubMed2001

Telomeric protein Pin2/TRF1 as an important ATM target in response to double strand DNA breaks.

ATM mutations are responsible for the genetic disease ataxia-telangiectasia (A-T). ATM encodes a protein kinase that is activated by ionizing radiation-induced double strand DNA breaks. Cells derived from A-T patients show many abnormalities, including accelerated telomere loss and hypersensitivity to ionizing radiation; they enter into mitosis and apoptosis after DNA damage. Pin2 was originally identified as a protein involved in G(2)/M regulation and is almost identical to TRF1, a telomeric protein that negatively regulates telomere elongation. Pin2 and TRF1, probably encoded by the same gene, PIN2/TRF1, are regulated during the cell cycle. Furthermore, up-regulation of Pin2 or TRF1 induces mitotic entry and apoptosis, a phenotype similar to that of A-T cells after DNA damage. These results suggest that ATM may regulate the function of Pin2/TRF1, but their exact relationship remains unknown. Here we show that Pin2/TRF1 coimmunoprecipitated with ATM, and its phosphorylation was increased in an ATM-dependent manner by ionizing DNA damage. Furthermore, activated ATM directly phosphorylated Pin2/TRF1 preferentially on the conserved Ser(219)-Gln site in vitro and in vivo. The biological significance of this phosphorylation is substantiated by functional analyses of the phosphorylation site mutants. Although expression of Pin2 and its mutants has no detectable effect on telomere length in transient transfection, a Pin2 mutant refractory to ATM phosphorylation on Ser(219) potently induces mitotic entry and apoptosis and increases radiation hypersensitivity of A-T cells. In contrast, Pin2 mutants mimicking ATM phosphorylation on Ser(219) completely fail to induce apoptosis and also reduce radiation hypersensitivity of A-T cells. Interestingly, the phenotype of the phosphorylation-mimicking mutants is the same as that which resulted from inhibition of endogenous Pin2/TRF1 in A-T cells by its dominant-negative mutants. These results demonstrate for the first time that ATM interacts with and phosphorylates Pin2/TRF1 and suggest that Pin2/TRF1 may be involved in the cellular response to double strand DNA breaks.

Amino Acid Sequence↗

PubMed2001

Binding and regulation of the transcription factor NFAT by the peptidyl prolyl cis-trans isomerase Pin1.

Nuclear factor of activated T cells (NFAT) plays a key role in T cell activation. The activation of NFAT involves calcium- and calcineurin-dependent dephosphorylation and nuclear translocation from the cytoplasm, a process that is opposed by protein kinases. We show here that the peptidyl prolyl cis-trans isomerase Pin1 interacts specifically with the phosphorylated form of NFAT. The NFAT-Pin1 interaction is mediated through the WW domain of Pin1 and the serine-proline-rich domains of NFAT. Furthermore, binding of Pin1 to NFAT inhibits the calcineurin-mediated dephosphorylation of NFAT in vitro, and overexpression of Pin1 in T cells inhibits calcium-dependent activation of NFAT in vivo. These results suggest a possible role for Pin1 in the regulation of NFAT in T cells.

Amino Acid Motifs↗

PubMed2001

Telomeric protein Pin2/TRF1 induces mitotic entry and apoptosis in cells with short telomeres and is down-regulated in human breast tumors.

Telomeres are essential for cell survival and have been implicated in the mitotic control. The telomeric protein Pin2/TRF1 controls telomere elongation and its expression is tightly regulated during cell cycle. We previously reported that overexpression of Pin2/TRF1 affects mitotic progression. However, the role of Pin2/TRF1 at the interface between cell division and cell survival remains to be determined. Here we show that overexpression of Pin2 induced apoptosis in cells containing short telomeres, but not in cells with long telomeres. Furthermore, before entering apoptosis, Pin2-expressing cells first accumulated in mitosis and strongly stained with the mitosis-specific MPM2 antibody. Moreover, Pin2-induced apoptosis is potentiated by arresting cells in mitosis, but suppressed by accumulating cells in G1. In addition, overexpression of Pin2 also resulted in activation of caspase-3, and its proapoptotic activity was significantly reduced by inhibition of caspase-3. These results indicate that up-regulation of Pin2/TRF1 can specifically induce entry into mitosis and apoptosis, likely via a mechanism related to activation of caspase-3. Significantly, we also found that, out of 51 human breast cancer tissues and 10 normal controls examined, protein levels of Pin2/TRF1 in tumors were significantly lower than in normal tissues, as detected by immunoblotting analysis and immunocytochemistry. Since down-regulation of Pin2/TRF1 allows cells to maintain long telomeres, these results suggest that down-regulation of Pin2/TRF1 may be important for cancer cells to extend their proliferative potential.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC.

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. Whereas the inhibition of Pin1 induces apoptosis, Pin1 is strikingly overexpressed in a subset of human tumours. Here we show that Pin1 regulates beta-catenin turnover and subcellular localization by interfering with its interaction with adenomatous polyposis coli protein (APC). A differential-display screen reveals that Pin1 increases the transcription of several beta-catenin target genes, including those encoding cyclin D1 and c-Myc. Manipulation of Pin1 levels affects the stability of beta-catenin in vitro. Furthermore, beta-catenin levels are decreased in Pin1-deficient mice but are increased and correlated with Pin1 overexpression in human breast cancer. Pin1 directly binds a phosphorylated Ser-Pro motif next to the APC-binding site in beta-catenin, inhibits its interaction with APC and increases its translocation into the nucleus. Thus, Pin1 is a novel regulator of beta-catenin signalling and its overexpression might contribute to the upregulation of beta-catenin in tumours such as breast cancer, in which APC or beta-catenin mutations are not common.

Adenomatous Polyposis Coli↗

PubMed2000

Functional replacement of the essential ESS1 in yeast by the plant parvulin DlPar13.

A functionally Pin1-like peptidyl-prolyl cis/trans isomerase (PPIase(1)) was isolated from proembryogenic masses (PEMs) of Digitalis lanata according to its enzymatic activity. Partial sequence analysis of the purified enzyme (DlPar13) revealed sequence homology to members of the parvulin family of PPIases. 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. Unlike Pin1-type enzymes it lacks the phosphoserine or phosphothreonine binding WW domain. Western blotting with anti-DlPar13 serum recognized the endogenous form in nucleic and cytosolic fractions of the plant cells. Since the PIN1 homologue ESS1 is an essential gene, complementation experiments in yeast were performed. When overexpressed in Saccharomyces cerevisiae DlPar13 is almost as effective as hPin1 in rescuing the temperature-sensitive phenotype caused by a mutation in ESS1. In contrast, the human parvulin hPar14 is not able to rescue the lethal phenotype of this yeast strain at nonpermissive temperatures. These results suggest a function for DlPar13 rather similar to parvulins of the Pin1-type.

Amino Acid Sequence↗

PubMed2000

Functional conservation of phosphorylation-specific prolyl isomerases in plants.

The phosphorylation-specific peptidyl prolyl cis/trans isomerase (PPIase) Pin1 in humans and its homologues in yeast and animal species play an important role in cell cycle regulation. These PPIases consist of an NH(2)-terminal WW domain that binds to specific phosphoserine- or phosphothreonine-proline motifs present in a subset of phosphoproteins and a COOH-terminal PPIase domain that specifically isomerizes the phosphorylated serine/threonine-proline peptide bonds. Here, we describe the isolation of MdPin1, a Pin1 homologue from the plant species apple (Malus domestica) and show that it has the same phosphorylation-specific substrate specificity and can be inhibited by juglone in vitro, as is the case for Pin1. A search in the plant expressed sequence tag data bases reveals that the Pin1-type PPIases are present in various plants, and there are multiple genes in one organism, such as soybean (Glycine max) and tomato (Lycopersicon esculentum). Furthermore, all these plant Pin1-type PPIases, including AtPin1 in Arabidopsis thaliana, do not have a WW domain, but all contain a four-amino acid insertion next to the phospho-specific recognition site of the active site. Interestingly, like Pin1, both MdPin1 and AtPin1 are able to rescue the lethal mitotic phenotype of a temperature-sensitive mutation in the Pin1 homologue ESS1/PTF1 gene in Saccharomyces cerevisiae. However, deleting the extra four amino acid residues abolished the ability of AtPin1 to rescue the yeast mutation under non-overexpression conditions, indicating that these extra amino acids may be important for mediating the substrate interaction of plant enzymes. Finally, expression of MdPin1 is tightly associated with cell division both during apple fruit development in vivo and during cell cultures in vitro. These results have demonstrated that phosphorylation-specific PPIases are highly conserved functionally in yeast, animal, and plant species. Furthermore, the experiments suggest that although plant Pin1-type enzymes do not have a WW domain, they may fulfill the same functions as Pin1 and its homologues do in other organisms.

Amino Acid Sequence↗

PubMed2000

Benzo(a)pyrene activates L1Md retrotransposon and inhibits DNA repair in vascular smooth muscle cells.

Benzo(a)pyrene (BaP) modulates vascular smooth muscle cells (vSMCs) from a quiescent to proliferative phenotype, a shift associated with activation of L1Md retrotransposon [K.P. Lu, K.S. Ramos, Biochem. Biophys. Res. Commun. 253 (1998) 828-833]. The present studies were conducted to evaluate L1Md activation profiles in murine vSMCs treated with BaP or its oxidative metabolites, and to screen for possible insertional mutations into p53 and retinoblastoma (RB) genes. We also sought to examine the profile of DNA damage and repair in BaP-treated vSMCs. Northern analysis revealed that BaP (0. 03-3microM), and its major reactive 7,8-diol metabolite (0. 03-3microM), activate L1Md gene in a concentration-dependent manner. Two other metabolites, 3-OH BaP and 3,6-BaP quinone (0.03-3microM), as well as hydrogen peroxide (25-75microM) also activated L1Md. No insertional mutations into either p53 or RB genes were observed in vSMCs treated with BaP in vitro, although a slight elevation of p53 mRNA was observed as early as 4h after chemical challenge. Treatment of vSMCs with 3 or 30microM BaP for 4h increased unscheduled DNA synthesis (UDS) 1.4- and 2.5-fold, respectively. Challenge with 0. 3microM BaP for 24h inhibited DNA repair capacity in vSMCs for up to 48h. These results demonstrate that BaP and its oxidative metabolites activate L1Md retrotransposon in vSMCs, which coupled to DNA damage and inhibition of DNA repair are part of the atherogenic response elicited by BaP and related hydrocarbons.

Animals↗

PubMed2000

Sustained activation of Ras/Raf/mitogen-activated protein kinase cascade by the tumor suppressor p53.

The p53 tumor suppressor gene can inhibit proliferation transiently, induce permanent cell-cycle arrest/senescence, or cause apoptosis depending on the cellular context. The mitogen-activated protein kinase (MAPK) cascade is known to play a crucial role in cell proliferation and differentiation. Moreover, the duration and intensity of MAPK activation can profoundly influence the biological response observed. We demonstrated that a sustained activation of MAPK cascade could be induced by wild-type p53 expression but not by p21(Waf1/Cip1). Furthermore, exposure of normal cells to DNA-damaging agents induced MAPK activation in a p53-dependent manner. Tumor-derived p53 mutants defective in DNA binding failed to activate MAPK, implying that p53 transcriptional activity is essential for this function. Finally, activation of MAPK by p53 was inhibited by expression of dominant-negative Ras (N17Ras) and Raf1 mutants, indicating that MAPK activation by p53 is mediated at a level upstream of Ras. All of these findings establish a biochemical link between p53 signaling and the Ras/Raf/MAPK cascade.

Cell Line, Transformed↗

PubMed2000

Actin-binding cellular proteins inside human immunodeficiency virus type 1.

Host proteins are incorporated both on and inside human immunodeficiency virus type 1 (HIV-1) virions. To identify cellular proteins inside HIV-1, virion preparations were treated by a protease-digestion technique that removes external host proteins, allowing for the study of the proteins inside the virus. Treated HIV-1 preparations were analyzed by immunoblot, high-pressure liquid chromatography, and protein sequence analyses. These analyses identified several cellular proteins inside HIV-1: elongation factor 1alpha, glyceraldehyde-3-phosphate dehydrogenase, HS-1, phosphatidylethanolamine-binding protein, Pin1, Lck, Nm23-H1, and the C-terminal tail of CD43. Several of these proteins were found as fragments of their full-sized proteins that appear to be generated by our protease treatment of the virions, the HIV-1 protease, or a cellular protease. Recent advances in cell biology and biochemistry have identified some of these proteins as actin-binding proteins. These results support the hypothesis that actin filaments are incorporated into the virion and may provide additional clues for the understanding of the interaction between viral and cellular proteins during assembly and budding.

Actins↗

PubMed2000

Phosphorylation-dependent prolyl isomerization: a novel cell cycle regulatory mechanism.

Protein phosphorylation by proline-directed protein kinases plays an essential role in triggering a programmed set of cell cycle events. We have recently isolated an essential and conserved mitotic regulator, Pin1. Pin1 is a phosphorylation-dependent prolyl isomerase that specifically isomerizes the phosphorylated serine/threonine-proline bond. Pin1 also binds and regulates the function of a conserved set of mitosis-specific phosphoproteins. These results suggest phosphorylation-dependent prolyl isomerization to be a novel cell cycle regulatory mechanism. This new post-translational regulation may allow the general increase in protein phosphorylation to be converted into the organised and programmed set of structural modifications that occur during mitosis. In addition, since inhibition of Pin1 induces mitotic arrest and apoptosis, Pin1 may be a potential new drug target.

Amino Acid Sequence↗