Phosphorylation of serine or threonine residue preceding proline (Ser/Thr-Pro) is a key regulatory mechanism. The conformation of certain phosphorylated Ser/Thr-Pro bonds is regulated specifically by the prolyl isomerase Pin1. Inhibition of Pin1 induces apoptosis and may contribute to neuronal death in Alzheimer's disease. It has been reported that Pin1 is strikingly overexpressed in a subset of human tumors. The differential display screen revealed that Pin1 increases the transcription of several target genes, including cyclin D1 and c-myc genes. Pin1 cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1. Pin1 also regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with adenomatous polyposis coli protein (APC). However, the analysis of Pin1 expression has not been demonstrated in human oral squamous cell carcinoma (OSCC). We examined the expression of Pin1 mRNA and protein in OSCC cell lines, and analyzed Pin1/cyclin D1/beta-catenin expression in OSCC clinical samples by immunohistochemical staining. We report that Pin1 is overexpressed in OSCC and its level correlates with cyclin D1 level. These results indicate that Pin1 is related to oncogenesis of OSCC.

Breast cancer stem-like cells (BCSC) have been implicated in tumor growth, metastasis, drug resistance, and relapse but druggable targets in appropriate subsets of this cell population have yet to be identified. Here we identify a fundamental role for the prolyl isomerase Pin1 in driving BCSC expansion, invasiveness, and tumorigenicity, defining it as a key target of miR200c, which is known to be a critical regulator in BCSC. Pin1 overexpression expanded the growth and tumorigenicity of BCSC and triggered epithelial-mesenchymal transition. Conversely, genetic or pharmacological inhibition of Pin1 reduced the abundance and self-renewal activity of BCSC. Moreover, moderate overexpression of miR200c-resistant Pin1 rescued the BCSC defect in miR200c-expressing cells. Genetic deletion of Pin1 also decreased the abundance and repopulating capability of normal mouse mammary stem cells. In human cells, freshly isolated from reduction mammoplasty tissues, Pin1 overexpression endowed BCSC traits to normal breast epithelial cells, expanding both luminal and basal/myoepithelial lineages in these cells. In contrast, Pin1 silencing in primary breast cancer cells freshly isolated from clinical samples inhibited the expansion, self-renewal activity, and tumorigenesis of BCSC in vitro and in vivo. Overall, our work demonstrated that Pin1 is a pivotal regulator acting downstream of miR200c to drive BCSC and breast tumorigenicity, highlighting a new therapeutic target to eradicate BCSC.

Different PIN-FORMED proteins (PINs) contribute to intercellular and intracellular auxin transport, depending on their distinctive subcellular localizations. Arabidopsis thaliana PINs with a long hydrophilic loop (HL) (PIN1 to PIN4 and PIN7; long PINs) localize predominantly to the plasma membrane (PM), whereas short PINs (PIN5 and PIN8) localize predominantly to internal compartments. However, the subcellular localization of the short PINs has been observed mostly for PINs ectopically expressed in different cell types, and the role of the HL in PIN trafficking remains unclear. Here, we tested whether a long PIN-HL can provide its original molecular cues to a short PIN by transplanting the HL. The transplanted long PIN2-HL was sufficient for phosphorylation and PM trafficking of the chimeric PIN5:PIN2-HL but failed to provide the characteristic polarity of PIN2. Unlike previous observations, PIN5 showed clear PM localization in diverse cell types where PIN5 is natively or ectopically expressed and even polar PM localization in one cell type. Furthermore, in the root epidermis, the subcellular localization of PIN5 switched from PM to internal compartments according to the developmental stage. Our results suggest that the long PIN-HL is partially modular for the trafficking behavior of PINs and that the intracellular trafficking of PIN is plastic depending on cell type and developmental stage.

The homolog of p53 gene, p63, encodes multiple p63 protein isoforms. TAp63 proteins contain an N-terminal transactivation domain similar to that of p53 and function as tumor suppressors; whereas ΔNp63 isoforms, which lack the intact N-terminal transactivation domain, are associated with human tumorigenesis. Accumulating evidence demonstrating the important roles of p63 in development and cancer development, the regulation of p63 proteins, however, is not fully understood. In this study, we show that peptidyl-prolyl isomerase Pin1 directly binds to and stabilizes TAp63α and ΔNp63α via inhibiting the proteasomal degradation mediated by E3 ligase WWP1. We further show that Pin1 specifically interacts with T538P which is adjacent to the P550PxY543 motif, and disrupts p63α-WWP1 interaction. In addition, while Pin1 enhances TAp63α-mediated apoptosis, it promotes ΔNp63α-induced cell proliferation. Furthermore, knockdown of Pin1 in FaDu cells inhibits tumor formation in nude mice, which is rescued by simultaneous knockdown of WWP1 or ectopic expression of ΔNp63α. Moreover, overexpression of Pin1 correlates with increased expression of ΔNp63α in human oral squamous cell carcinoma samples. Together, these results suggest that Pin1-mediated modulation of ΔNp63α may have a causative role in tumorigenesis.

The protein flotillin-1 is associated with the 'lipid rafts', that is, membrane microdomains that are enriched in cholesterol and sphingolipids. We compared flotillin-1 immunoreactivity in the hippocampus, amygdala and isocortex (Brodmann area 22) of six controls and 13 Alzheimer's disease (AD) cases (10 sporadic and three familial). A diffuse labelling of the neuropil was observed in most of the samples. The intensity of this labelling was not correlated with the density of neurofibrillary tangles (NFT) or of senile plaques. Some neuronal cell bodies were diffusely labelled in patients as in controls. Immunostained granular bodies were found in the cell body of a few neurones. The density of neuronal profiles containing large granular bodies (diameter>> or =2 microm) was significantly higher in AD cases and was correlated with the density of NFTs in the three regions that were studied. Sections stained by double immunofluorescence methods and examined with confocal microscopy suggested that flotillin-1 accumulated most often in tangle-bearing neurones (76% of flotillin-1-positive neurones contained a NFT). Flotillin-1 immunoreactivity, even when found in a tangle-bearing neurone, was not colocalized with tau protein indicating that the two proteins were not in close contact and probably in different subcellular compartments. Flotillin-1-positive granular bodies were also found in neurones containing Pin1-positive vesicles but were not colocalized with them. Flotillin-1 immunoreactivity was colocalized with cathepsin D, a lysosomal marker. These data indicate that flotillin-1, a marker of rafts, accumulates in lysosomes of tangle-bearing neurones in the course of AD.

In Arabidopsis, leaves and flowers form cyclically in the shoot meristem periphery and are triggered by local accumulations of the plant hormone auxin. Auxin maxima are established by the auxin efflux carrier PIN-formed1 (PIN1). During organ formation, two distinct types of PIN1 polarization occur. First, convergence of PIN1 polarity in the surface of the meristem creates local auxin peaks. Second, basipetal PIN1 polarization causes auxin to move away from the surface in the middle of an incipient organ primordium, thought to contribute to vascular formation. Several mathematical models have been developed in attempts to explain the PIN1 localization pattern. However, the molecular mechanisms that control these dynamic changes are unknown. Here, we show that loss-of-function in the MACCHI-BOU 4 (MAB4) family genes, which encode nonphototropic hypocotyl 3-like proteins and regulate PIN endocytosis, cause deletion of basipetal PIN1 polarization, resulting in extensive auxin accumulation all over the meristem surface from lack of a sink for auxin. These results indicate that the MAB4 family genes establish inward auxin transport from the L1 surface of incipient organ primordia by basipetal PIN1 polarization, and that this behavior is essential for the progression of organ development. Furthermore, the expression of the MAB4 family genes depends on auxin response. Our results define two distinct molecular mechanisms for PIN1 polarization during organ development and indicate that an auxin response triggers the switching between these two mechanisms.

Spermatogonial stem cells (SSCs) undergo self-renewal divisions to support spermatogenesis throughout life. Although several positive regulators of SSC self-renewal have been discovered, little is known about the negative regulators. Here, we report that F-box and WD-40 domain protein 7 (FBXW7), a component of the Skp1-Cullin-F-box-type ubiquitin ligase, is a negative regulator of SSC self-renewal. FBXW7 is expressed in undifferentiated spermatogonia in a cell cycle-dependent manner. Although peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1), essential for spermatogenesis, is thought to destroy FBXW7, Pin1 depletion decreased FBXW7 expression. Spermatogonial transplantation showed that Fbxw7 overexpression compromised SSC activity whereas Fbxw7 deficiency enhanced SSC colonization and caused accumulation of undifferentiated spermatogonia, suggesting that the level of FBXW7 is critical for self-renewal and differentiation. Screening of putative FBXW7 targets revealed that Fbxw7 deficiency up-regulated myelocytomatosis oncogene (MYC) and cyclin E1 (CCNE1). Although depletion of Myc/Mycn or Ccne1/Ccne2 compromised SSC activity, overexpression of Myc, but not Ccne1, increased colonization of SSCs. These results suggest that FBXW7 regulates SSC self-renewal in a negative manner by degradation of MYC.

Upon hormonal signaling, ovules develop as lateral organs from the placenta. Ovule numbers ultimately determine the number of seeds that develop, and thereby contribute to the final seed yield in crop plants. We demonstrate here that CUP-SHAPED COTYLEDON 1 (CUC1), CUC2 and AINTEGUMENTA (ANT) have additive effects on ovule primordia formation. We show that expression of the CUC1 and CUC2 genes is required to redundantly regulate expression of PINFORMED1 (PIN1), which in turn is required for ovule primordia formation. Furthermore, our results suggest that the auxin response factor MONOPTEROS (MP/ARF5) may directly bind ANT, CUC1 and CUC2 and promote their transcription. Based on our findings, we propose an integrative model to describe the molecular mechanisms of the early stages of ovule development.

To probe the conformational requirements of loop 1 in the Pin1 WW domain, the residues at the i + 2 and i + 3 positions of a beta-turn within this loop were replaced by dPro-Gly and Asn-Gly, which are known to prefer the conformations required at the i + 1 and i + 2 positions of type II' and type I' beta-turns. Conformational specificity or lack thereof was further examined by incorporating into the i + 2 and i + 3 positions a non-alpha-amino acid-based beta-turn mimetic (4-(2'-aminoethyl)-6-dibenzofuran propionic acid residue, 1), which was designed to replace the i + 1 and i + 2 positions of beta-turns. All these Pin WW variants are monomeric and folded as discerned by analytical ultracentrifugation, NMR, and CD. They exhibit cooperative two-state transitions and display thermodynamic stability within 0.5 kcal/mol of the wild-type WW domain, demonstrating that the acquisition of native structure and stability does not require a specific sequence and, by extension, conformation within loop 1. However, it could be that these loop 1 mutations alter the kinetics of antiparallel beta-sheet folding, which will be addressed by subsequent kinetic studies.

MicroRNAs (miRNAs) are small, noncoding RNAs that post-transcriptionally regulate expression of their target messenger RNAs. We recently demonstrated that primary miRNA transcripts (pri-miRNAs) retained at transcription sites are processed with enhanced efficiency, suggesting that pri-miRNA processing is coupled to transcription in mammalian cells. We also observed that transiently expressed pri-miRNAs accumulate in nuclear foci with splicing factor SC35 and Microprocessor components, Drosha and DGCR8. Here, we show that pri-miRNAs containing a self-cleaving hepatitis delta ribozyme accumulate in the nucleoplasm after release from their transcription sites, but are not efficiently processed. Pri-miRNAs with ribozyme-generated 3' ends do not localize to SC35-containing foci, whereas cleaved and polyadenylated pri-miRNA transcripts with or without the pre-miRNA hairpin do. Pri-miRNA/SC35 foci contain a number of proteins normally associated with SC35 domains, including ASF/SF2, PABII, and the prolyl isomerase, Pin1. In contrast, RNA polymerase II and PM/Scl-100 do not strongly colocalize with pri-miRNAs in SC35-containing foci. These data argue that pri-miRNA/SC35-containing foci are not major sites of pri-miRNA processing and that pri-miRNA processing is coupled to transcription. We discuss the implications of our findings relative to recent insights into miRNA biogenesis, mRNA metabolism, and the nuclear organization of gene expression.

APOBEC3G (A3G) is a cytidine deaminase that restricts human immunodeficiency virus type 1 (HIV-1) replication. HIV-1 synthesizes a viral infectivity factor (Vif) to counter A3G restriction. Currently, it is poorly understood how A3G expression/activity is regulated by cellular factors. Here, we show that the prolyl isomerase Pin1 protein modulates A3G expression. Pin1 was found to be an A3G-interacting protein that reduces A3G expression and its incorporation into HIV-1 virion, thereby limiting A3G-mediated restriction of HIV-1. Intriguingly, HIV-1 infection modulates the phosphorylation state of Pin1, enhancing its ability to moderate A3G activity. These new findings suggest a potential Vif-independent way for HIV-1 to moderate the cellular action of A3G.

The prominent characteristics of pluripotent stem cells are their unique capacity to self-renew and pluripotency. Although pluripotent stem cell proliferation is maintained by specific intracellular phosphorylation signaling events, it has not been well characterized how the resulting phosphorylated proteins are subsequently regulated. We here report that the peptidylprolyl isomerase Pin1 is indispensable for the self-renewal and maintenance of pluripotent stem cells via the regulation of phosphorylated Oct4 and other substrates. Pin1 expression was found to be up-regulated upon the induction of induced pluripotent stem (iPS) cells, and the forced expression of Pin1 with defined reprogramming factors was observed to further enhance the frequency of iPS cell generation. The inhibition of Pin1 activity significantly suppressed colony formation and induced the aberrant differentiation of human iPS cells as well as murine ES cells. We further found that Pin1 interacts with the phosphorylated Ser(12)-Pro motif of Oct4 and that this in turn facilitates the stability and transcriptional activity functions of Oct4. Our current findings thus uncover an atypical role for Pin1 as a putative regulator of the induction and maintenance of pluripotency via the control of phosphorylation signaling. These data suggest that the manipulation of Pin1 function could be a potential strategy for the stable induction and proliferation of human iPS cells.

Promyelocytic leukemia protein (PML) was originally identified as part of a chromosomal translocation that contributes to the development of acute promyelocytic leukemia (APL). Since its discovery, PML has been found to play diverse roles in different cellular processes. Notably, PML has anti-proliferative and pro-apoptotic activity that supports its role as a tumor suppressor. We have previously shown that the peptidyl-prolyl isomerase Pin1 is able to affect cell proliferation and hydrogen peroxide (H(2)O(2))-mediated cell death through modulation of the steady-state levels of PML. We have extended these studies to show that the interaction between PML and Pin1 is targeted by multiple extracellular signals in the cell. We show that H(2)O(2) up-regulates and IGF-1 down-regulates PML expression in a Pin1-dependent manner. Interestingly, we found that H(2)O(2)- and IGF-1-mediated alteration in PML accumulation regulate MDA-MB-231 cell migration. Furthermore, we show that the control of cell migration by PML, and thus H(2)O(2) and IGF-1, results from PML-dependent decreased expression of integrin beta1 (ITGB1). Knockdown of Pin1 leads to decreased cell migration, lower levels of ITGB1 expression and resistance to IGF-1- and H(2)O(2)-induced changes in cell migration and ITGB1 expression. Taken together, our work identifies PML as a common target for H(2)O(2) and IGF-1 and supports a novel tumor suppressive role for PML in controlling cell migration through the expression of ITGB1.

The aims of this study were to investigate the expression levels of beta-catenin, Pin1 and cyclin D1 in salivary adenoid cystic carcinomas (SACC ) and to evaluate its clinical importance, furthermore, to elucidate whether beta-catenin expression was aberrant in SACC and whether Pin1 was involved in aberrant beta-catenin and cyclin D1 expression. The expression of Pin1, beta-catenin and cyclin D1 were examined in the specimens of 65 patients with SACC by immunohistochemistry, protein and mRNA expressions were detected by western blotting and RT-PCR in four SACC cell lines. Pin1 was overexpressed in 51 cases of SACC (78%), and high levels of Pin1 expression correlated with cyclin D1 positive expression (p = 0.02). Fourteen (22%) cases showed positive immunoreactivity for beta-catenin protein in the nuclear/cytoplasmic fraction in tumor tissues, which was defined as cytoplasm/nucleus staining, among which quite evident nuclear expression of beta-catenin was detected in six cases (9%), while cyclin D1 positive expression was detected in 41 cases of SACC (63%). Reduced membranous expression of beta-catenin was detected in the cases with metastasis (11/14). Theses results suggest that Pin1 and Wnt signalling pathway are activated in SACC and may play a pivotal role in SACC carcinogenesis and metastasis.

Under normal conditions, the proline-directed serine/threonine residues of neurofilament tail-domain repeats are exclusively phosphorylated in axons. In pathological conditions such as amyotrophic lateral sclerosis (ALS), motor neurons contain abnormal perikaryal accumulations of phosphorylated neurofilament proteins. The precise mechanisms for this compartment-specific phosphorylation of neurofilaments are not completely understood. Although localization of kinases and phosphatases is certainly implicated, another possibility involves Pin1 modulation of phosphorylation of the proline-directed serine/threonine residues. Pin1, a prolyl isomerase, selectively binds to phosphorylated proline-directed serine/threonine residues in target proteins and isomerizes cis isomers to more stable trans configurations. In this study we show that Pin1 associates with phosphorylated neurofilament-H (p-NF-H) in neurons and is colocalized in ALS-affected spinal cord neuronal inclusions. To mimic the pathology of neurodegeneration, we studied glutamate-stressed neurons that displayed increased p-NF-H in perikaryal accumulations that colocalized with Pin1 and led to cell death. Both effects were reduced upon inhibition of Pin1 activity by the use of an inhibitor juglone and down-regulating Pin1 levels through the use of Pin1 small interfering RNA. Thus, isomerization of lys-ser-pro repeat residues that are abundant in NF-H tail domains by Pin1 can regulate NF-H phosphorylation, which suggests that Pin1 inhibition may be an attractive therapeutic target to reduce pathological accumulations of p-NF-H.

Tomato (Solanum lycopersicum) has a unique resistance gene, Mi-1, that confers resistance to animals from distinct taxa, nematodes, and piercing and sucking insects. Mi-1 encodes a protein with a nucleotide-binding site and leucine-rich repeat motifs. Early in the potato aphid (Macrosiphum euphorbiae)--tomato interactions, aphid feeding induces the expression of the jasmonic acid (JA)-regulated proteinase inhibitor genes, Pin1 and Pin2. The jail-1 (jasmonic acid insensitive 1) tomato mutant, which is impaired in JA perception, was used to gain additional insight into the JA signaling pathway and its role in the Mi-1-mediated aphid resistance. The jail-1 mutant has a deletion in the Coil gene that encodes a putative F-box protein. In this study, aphid colonization, survival, and fecundity were compared on wild-type tomato and jail-1 mutant. In choice assays, the jail-1 mutant showed higher colonization by potato aphids compared with wild-type tomato. In contrast, no-choice assays showed no difference in potato aphid survival or fecundity between jail-1 and the wild-type parent. Plants homozygous for Mi-1 and for the jail mutation were not compromised in resistance to potato aphids, using either choice or no-choice assays. In addition, the accumulation of JA-regulated Pin1 transcripts after aphid feeding was Coil dependent. Taken together, these data indicate that, although potato aphids activate Coil-dependent defense response in tomato, this response is not required for Mi-1-mediated resistance to aphids.

BRAHMA (BRM), a SWI/SNF chromatin remodeling ATPase, is essential for the transcriptional reprogramming associated with development and cell differentiation in Arabidopsis thaliana. In this study, we show that loss-of-function mutations in BRM led to defective maintenance of the root stem cell niche, decreased meristematic activity, and stunted root growth. Mutations of BRM affected auxin distribution by reducing local expression of several PIN-FORMED (PIN) genes in the stem cells and impaired the expression of the stem cell transcription factor genes PLETHORA (PLT1) and PLT2. Chromatin immunoprecipitation assays showed that BRM could directly target to the chromatin of PIN1, PIN2, PIN3, PIN4, and PIN7. In addition, genetic interaction assays indicate that PLTs acted downstream of BRM, and overexpression of PLT2 partially rescued the stem cell niche defect of brm mutants. Taken together, these results support the idea that BRM acts in the PLT pathway to maintain the root stem cell niche by altering the expression of PINs.

The interaction between the neuronal Tau protein and the Pin1 prolyl cis/trans-isomerase is dependent on the phosphorylation state of the former. The interaction site was mapped to the unique phospho-Thr231-Pro232 motif, despite the presence of many other Thr/Ser-Pro phosphorylation sites in Tau and structural evidence that the interaction site does not significantly extend beyond those very two residues. We demonstrate here by NMR and fluorescence mapping that the Alzheimer's disease specific epitope centered around the phospho-Thr212-Pro213 motif is also an interaction site, and that the sole phospho-Thr-Pro motif is already sufficient for interaction. Because a detectable fraction of the Pro213 amide bond in the peptide centered around the phospho-Thr212-Pro213 motif is in the cis conformation, catalysis of the isomerization by the catalytic domain of Pin1 could be investigated via NMR spectroscopy.

It is an emerging view that in many cases cell signalling relies on slow conformational interconversions of the backbone of key proteins as exemplified by the prolyl cis/trans isomerization, and that prolyl cis/trans isomerases (PPIases), such as cyclophilins, FK506-binding proteins and the parvulin-like Pin1, serve to integrate temporally and spatially protein conformers with signalling events. The causal relationship between prolyl cis/trans isomerization catalysis, malignant transformation and tumour progression is not yet fully understood because of the pleiotropic biochemical effects characterizing these enzymes. However, recent studies on the role of cyclophilins and Pin1 indicate that PPIases utilize isomerization catalysis on client proteins under physiological and pathophysiological conditions. This knowledge could offer new cancer intervention strategies based on the development of isoenzyme-specific, tissue-specific and organelle-specific PPIase inhibitors.

The plant hormone auxin and its directional transport are known to play a crucial role in defining the embryonic axis and subsequent development of the body plan. Although the role of PIN auxin efflux transporters has been clearly assigned during embryonic shoot and root specification, the role of the auxin influx carriers AUX1 and LIKE-AUX1 (LAX) proteins is not well established. Here, we used chemical and genetic tools on Brassica napus microspore-derived embryos and Arabidopsis thaliana zygotic embryos, and demonstrate that AUX1, LAX1 and LAX2 are required for both shoot and root pole formation, in concert with PIN efflux carriers. Furthermore, we uncovered a positive-feedback loop between MONOPTEROS (ARF5)-dependent auxin signalling and auxin transport. This MONOPTEROS-dependent transcriptional regulation of auxin influx (AUX1, LAX1 and LAX2) and auxin efflux (PIN1 and PIN4) carriers by MONOPTEROS helps to maintain proper auxin transport to the root tip. These results indicate that auxin-dependent cell specification during embryo development requires balanced auxin transport involving both influx and efflux mechanisms, and that this transport is maintained by a positive transcriptional feedback on auxin signalling.

The important roles of a nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) are widely accepted in various biological processes as well as metabolic diseases. Despite the worldwide quest for pharmaceutical manipulation of PPARgamma activity through the ligand-binding domain, very little information about the activation mechanism of the N-terminal activation function-1 (AF-1) domain. Here, we demonstrate the molecular and structural basis of the phosphorylation-dependent regulation of PPARgamma activity by a peptidyl-prolyl isomerase, Pin1. Pin1 interacts with the phosphorylated AF-1 domain, thereby inhibiting the polyubiquitination of PPARgamma. The interaction and inhibition are dependent upon the WW domain of Pin1 but are independent of peptidyl-prolyl cis/trans-isomerase activity. Gene knockdown experiments revealed that Pin1 inhibits the PPARgamma-dependent gene expression in THP-1 macrophage-like cells. Thus, our results suggest that Pin1 regulates macrophage function through the direct binding to the phosphorylated AF-1 domain of PPARgamma.

Plants interact with root microbes via chemical signaling, which modulates competence or symbiosis. Although several volatile organic compounds (VOCs) from fungi may affect plant growth and development, the signal transduction pathways mediating VOC sensing are not fully understood. 6-pentyl-2H-pyran-2-one (6-PP) is a major VOC biosynthesized by Trichoderma spp. which is probably involved in plant-fungus cross-kingdom signaling. Using microscopy and confocal imaging, the effects of 6-PP on root morphogenesis were found to be correlated with DR5:GFP, DR5:VENUS, H2B::GFP, PIN1::PIN1::GFP, PIN2::PIN2::GFP, PIN3::PIN3::GFP and PIN7::PIN7::GFP gene expression. A genetic screen for primary root growth resistance to 6-PP in wild-type seedlings and auxin- and ethylene-related mutants allowed identification of genes controlling root architectural responses to this metabolite. Trichoderma atroviride produced 6-PP, which promoted plant growth and regulated root architecture, inhibiting primary root growth and inducing lateral root formation. 6-PP modulated expression of PIN auxin-transport proteins in a specific and dose-dependent manner in primary roots. TIR1, AFB2 and AFB3 auxin receptors and ARF7 and ARF19 transcription factors influenced the lateral root response to 6-PP, whereas EIN2 modulated 6-PP sensing in primary roots. These results indicate that root responses to 6-PP involve components of auxin transport and signaling and the ethylene-response modulator EIN2.

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus etiologically causal of adult T-cell leukemia (ATL). The virus encodes a Tax oncoprotein that functions in transcriptional regulation, cell cycle control, and transformation. ATL is a highly virulent cancer that is resistant to chemotherapeutic treatments. To understand this disease better, it is important to comprehend how HTLV-1 promotes cellular growth and survival. Tax activation of NF-kappaB is important for the proliferation and transformation of virus-infected cells. We show here that prolyl isomerase Pin1 is over expressed in HTLV-1 cell lines; Pin1 binds Tax and regulates Tax-induced NF-kappaB activation.

Recent studies have demonstrated the re-emergence of cell cycle proteins in brain as patients progress from the early stages of mild cognitive impairment (MCI) into Alzheimer's disease (AD). Oxidative stress markers present in AD have also been shown to be present in MCI brain suggesting that these events occur in early stages of the disease. The levels of key cell cycle proteins, such as CDK2, CDK5, cyclin G1, and BRAC1 have all been found to be elevated in MCI brain compared to age-matched control. Further, peptidyl prolyl cis-trans isomerase (Pin1), a protein that plays an important role in regulating the activity of key proteins, such as CDK5, GSK3-β, and PP2A that are involved in both the phosphorylation state of Tau and in the cell cycle, has been found to be oxidatively modified and downregulated in both AD and MCI brain. Hyperphosphorylation of Tau then results in synapse loss and the characteristic Tau aggregation as neurofibrillary tangles, an AD hallmark. In this review, we summarized the role of cell cycle dysregulation in the progression of disease from MCI to AD. Based on the current literature, it is tempting to speculate that a combination of oxidative stress and cell cycle dysfunction conceivably leads to neurodegeneration.