Relationship between Personality Traits and Subjective Well-Being in Emerging Adulthood: Moderating Role of Independent and Interdependent Self-Construal.

During emerging adulthood, individuals' subjective well-being declines owing to challenges regarding identity, work, and romantic relationships. Although the relationships among personality traits, self-construal, and well-being have been examined, studies have focused on personal rather than relational subjective well-being. Furthermore, self-construal's moderating effect on the relationship between personality traits and subjective well-being remains unclear. Therefore, this study examined the relationships among the Big-five personality traits and subjective well-being (life satisfaction, happiness, and interdependent happiness) and the moderating effect of self-construal among 1548 Japanese emerging adults (Mage = 22.24, SD = 1.01). Regression analysis indicated that all aspects of subjective well-being were negatively associated with neuroticism and positively associated with extraversion, independent and interdependent self-construal. Further, agreeableness was positively associated with personal and relational well-being. Independent or interdependent self-construal can moderate the relationships between neuroticism, extraversion, and agreeableness and subjective well-being. Overall, these findings provide valuable insights for improving Japanese emerging adults' well-being.

Disabled-1 dorsal horn spinal cord neurons co-express Lmx1b and function in nociceptive circuits.

The Reelin-signaling pathway is essential for correct neuronal positioning within the central nervous system. Mutant mice with a deletion of Reelin, its lipoprotein receptors, or its intracellular adaptor protein Disabled-1 (Dab1), exhibit nociceptive abnormalities: thermal (heat) hyperalgesia and reduced mechanical sensitivity. To determine dorsal horn alterations associated with these nociceptive abnormalities, we first characterized the correctly positioned Dab1 neurons in wild-type and mispositioned neurons in Reelin-signaling pathway mutant lumbar spinal cord. Using immunofluorescence, we found that 70% of the numerous Dab1 neurons in Reln+/+ laminae I-II and 67% of those in the lateral reticulated area and lateral spinal nucleus (LSN) co-express the LIM-homeobox transcription factor 1 beta (Lmx1b), an excitatory glutamatergic neuron marker. Evidence of Dab1- and Dab1-Lmx1b neuronal positioning errors was found within the isolectin B4 terminal region of Reln-/- lamina IIinner and in the lateral reticulated area and LSN, where about 50% of the Dab1-Lmx1b neurons are missing. Importantly, Dab1-Lmx1b neurons in laminae I-II and the lateral reticulated area express Fos after noxious thermal or mechanical stimulation and thus participate in these circuits. In another pain relevant locus - the lateral cervical nucleus (LCN), we also found about a 50% loss of Dab1-Lmx1b neurons in Reln-/- mice. We suggest that extensively mispositioned Dab1 projection neurons in the lateral reticulated area, LSN, and LCN and the more subtle positioning errors of Dab1 interneurons in laminae I-II contribute to the abnormalities in pain responses found in Reelin-signaling pathway mutants.

Motivation to lead in Japan: validation of a Japanese version of the motivation to lead scale.

Introduction: This study aimed to develop a Japanese version of the motivation to lead (MTL) scale consisting of three factors-affective-identity MTL, non-calculative MTL, and social-normative MTL-and examine its construct validity and reliability. Methods: The participants comprised 500 university students and 500 employees aged 20-29 years registered with a Japanese research company. Results: Based on a confirmatory factor analysis, the three-factor model was found to be appropriate for the Japanese context. The measurement invariance analyses indicated scalar invariance between students and employees and between men and women. Finally, the correlation analysis with the Big Five personality traits conducted to examine construct validity indicated that affective-identity MTL and social-normative MTL had significant relationships with all five traits (extraversion, agreeableness, conscientiousness, open-mindedness, and negative emotionality). Although non-calculative MTL was not significantly correlated, it can be interpreted in the Japanese context. Discussion: The results indicate the adequate construct validity and reliability of the Japanese version of the MTL scale. These findings hold significant implications for leadership development and selection in Japan, highlighting the motivational factors that drive effective leadership.

Self-assembly of a poly(glutamate) dendrimer: solvent-dependent expression of molecular chirality and a [2 + 2] photocrosslinking reaction.

Upon photoirradiation of a stilbene-cored poly(glutamate) dendrimer, the photocrosslinking reaction preferentially occurred to produce the [2 + 2] cycloadduct in benzene. In addition, blue-shifted absorption spectra and a bisignate circular dichroism (CD) signal were observed, indicating that the aggregates of the stilbene core were chiral.

Jomthonic acid , a modified amino acid from a soil-derived Streptomyces.

Jomthonic acid A (1), a new modified amino acid, was isolated from the culture broth of a soil-derived actinomycete of the genus Streptomyces. The structure and absolute configuration of 1 were determined by spectroscopic analyses and chemical conversion. Jomthonic acid A (1) induced differentiation of preadipocytes into mature adipocytes at 2-50 µM.

Validation of the Japanese version of the revised version of the compound psychological capital scale (CPC-12R).

This study developed a Japanese version of the Revised Version of the Compound Psychological Capital Scale (CPC-12R) and tested its reliability and construct validity. The participants were 1,000 young adults (500 university students and 500 employees) recruited through an internet survey. Confirmatory factor analysis showed that the four first-order factors (hope, optimism, resilience, and self-efficacy) and one second-order factor (PsyCap) model of the previous study is appropriate for the Japanese context. In addition, Cronbach's α and omega-higher-order of CPC-12R were sufficient. The measurement invariance analysis suggested sufficient scalar invariances for the employees and university students and across genders. The Japanese version of the CPC-12R had moderate positive correlations with job satisfaction, work engagement, conscientiousness, and extraversion, as well as a moderate negative correlation with negative emotionality. These findings provide evidence for sufficient reliability and construct validity of the Japanese version of the CPC-12R.

Effects of Anti-Receptor Activator of Nuclear Factor Kappa B Ligand Antibody and Zoledronic Acid on Periapical Lesion Development in Mice.

INTRODUCTION: Antiresorptive drugs are widely used to treat osteoporosis and other systemic bone diseases, although their efficacy for local bone resorption after localized inflammation has not been fully elucidated. We examined the effects of an anti-receptor activator of nuclear factor kappa B ligand (RANKL) antibody and the bisphosphonate zoledronic acid (ZOL) on periapical lesion (PL) development in mice. METHODS: Dental pulp of lower first molars in mice was removed, with the exposed dental pulp chambers left open to the oral environment to induce apical periodontitis. An anti-RANKL antibody or ZOL was intraperitoneally injected once per week until postoperative day 21, and then micro-computed tomographic imaging and histologic analyses were performed. RESULTS: PL enlargement was inhibited by both the anti-RANKL antibody and ZOL in a dose-dependent manner, and a reduction of inflammatory cell infiltration in apical tissues inhibited periapical bone resorption. The anti-RANKL antibody decreased the number of osteoclasts in periapical tissues, whereas ZOL suppressed periapical bone resorption with osteoclast numbers maintained. Although the administration of each of the antiresorptive drugs increased femoral bone mass, femoral bone mineral density in the PL group was lower compared with the sham-operated group. CONCLUSIONS: These results suggest that an antiresorptive drug administered systemically is distributed to areas of local inflammation in the jaw can prevent PL development.

Neural crest-derived cells possess differentiation potential to keratinocytes in the process of wound healing.

Neural crest-derived cells (NCDCs), which exist as neural crest cells during the fetal stage and differentiate into palate cells, also exist in adult palate tissues, though with unknown roles. In the present study, NCDCs were labeled with EGFP derived from P0-Cre/CAG-CAT-EGFP (P0-EGFP) double transgenic mice, then their function in palate mucosa wound healing was analyzed. As a palate wound healing model, left-side palate mucosa of P0-EGFP mice was resected, and stem cell markers and keratinocyte markers were detected in healed areas. NCDCs were extracted from normal palate mucosa and precultured with stem cell media for 14 days, then were differentiated into keratinocytes or osteoblasts to analyze pluripotency. The wound healing process started with marginal mucosal regeneration on day two and the entire wound area was lined by regenerated mucosa with EGFP-positive cells (NCDCs) on day 28. EGFP-positive cells comprised approximately 60% of cells in healed oral mucosa, and 65% of those expressed stem cell markers (Sca-1+, PDGFRα+) and 30% expressed a keratinocyte marker (CK13+). In tests of cultured palate mucosa cells, approximately 70% of EGFP-positive cells expressed stem cell markers (Sca-1+, PDGFRα+). Furthermore, under differentiation inducing conditions, cultured EGFP-positive cells were successfully induced to differentiate into keratinocytes and osteoblasts. We concluded that NCDCs exist in adult palate tissues as stem cells and have potential to differentiate into various cell types during the wound healing process.

Nobiletin, a citrus polymethoxyflavonoid, suppresses multiple angiogenesis-related endothelial cell functions and angiogenesis in vivo.

Nobiletin is a citrus polymethoxyflavonoid that suppresses tumor growth and metastasis, both of which depend on angiogenesis. We recently identified nobiletin as a cell differentiation modulator. Because cell differentiation is a critical event in angiogenesis, it might be possible that nobiletin could exhibit antiangiogenic activity, resulting in suppression of these tumor malignant properties. To verify this possibility, we examined the antiangiogenic effects of nobiletin in vitro and in vivo. Nobiletin had concentration-dependent inhibitory effects on multiple functions of angiogenesis-related endothelial cells (EC); it suppressed the proliferation, migration and tube formation on matrigel of human umbilical vein EC (HUVEC) stimulated with endothelial cell growth supplement (ECGS), a mixture of acidic and basic fibroblast growth factors (FGFs). Gelatin zymography and northern blotting revealed that nobiletin suppressed pro-matrix metalloproteinase-2 (proMMP-2) production and MMP-2 mRNA expression in ECGS-stimulated HUVEC. Nobiletin also downregulated cell-associated plasminogen activator (PA) activity and urokinase-type PA mRNA expression. Furthermore, nobiletin inhibited angiogenic differentiation induced by vascular endothelial growth factor and FGF, an in vitro angiogenesis model. This inhibition was accompanied by downregulation of angiogenesis-related signaling molecules, such as extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase, and transcriptional factors (c-Jun and signal transducer and activator of transcription 3), and activation of the caspase pathway. In a chick embryo chorioallantoic membrane assay, nobiletin showed an antiangiogenic activity, the ID(50) value being 10µg (24.9nmol) per egg. These results indicate that nobiletin is a novel antiangiogenic compound that exhibits its activity through combined inhibition of multiple angiogenic EC functions.

Pre-clinical study of induced pluripotent stem cell-derived dopaminergic progenitor cells for Parkinson's disease.

Induced pluripotent stem cell (iPSC)-derived dopaminergic (DA) neurons are an expected source for cell-based therapies for Parkinson's disease (PD). The regulatory criteria for the clinical application of these therapies, however, have not been established. Here we show the results of our pre-clinical study, in which we evaluate the safety and efficacy of dopaminergic progenitors (DAPs) derived from a clinical-grade human iPSC line. We confirm the characteristics of DAPs by in vitro analyses. We also verify that the DAP population include no residual undifferentiated iPSCs or early neural stem cells and have no genetic aberration in cancer-related genes. Furthermore, in vivo studies using immunodeficient mice reveal no tumorigenicity or toxicity of the cells. When the DAPs are transplanted into the striatum of 6-OHDA-lesioned rats, the animals show behavioral improvement. Based on these results, we started a clinical trial to treat PD patients in 2018.

Trophic factors are essential for the survival of grafted oligodendrocyte progenitors and for neuroprotection after perinatal excitotoxicity.

The consequences of neonatal white matter injury are devastating and represent a major societal problem as currently there is no cure. Prematurity, low weight birth and maternal pre-natal infection are the most frequent causes of acquired myelin deficiency in the human neonate leading to cerebral palsy and cognitive impairment. In the developing brain, oligodendrocyte (OL) maturation occurs perinatally, and immature OLs are particularly vulnerable. Cell replacement therapy is often considered a viable option to replace progenitors that die due to glutamate excitotoxicity. We previously reported directed specification and mobilization of endogenous committed and uncommitted neural progenitors by the combination of transferrin and insulin growth factor 1 (TSC1). Here, considering cell replacement and integration as therapeutic goals, we examined if OL progenitors (OLPs) grafted into the brain parenchyma of mice that were subjected to an excitotoxic insult could rescue white matter injury. For that purpose, we used a well-established model of glutamate excitotoxic injury. Four-day-old mice received a single intraparenchymal injection of the glutamate receptor agonist N-methyl-D-aspartate alone or in conjunction with TSC1 in the presence or absence of OLPs grafted into the brain parenchyma. Energetics and expression of stress proteins and OL developmental specific markers were examined. A comparison of the proteomic profile per treatment was also ascertained. We found that OLPs did not survive in the excitotoxic environment when grafted alone. In contrast, when combined with TSC1, survival and integration of grafted OLPs was observed. Further, energy metabolism in OLPs was significantly increased by N-methyl-D-aspartate and modulated by TSC1. The proteomic profile after the various treatments showed elevated ubiquitination and stress/heat shock protein 90 in response to N-methyl-D-aspartate. These changes were reversed in the presence of TSC1 and ubiquitination was decreased. The results obtained in this pre-clinical study indicate that the use of a combinatorial intervention including both trophic support and healthy OLPs constitutes a promising approach for long-term survival and successful graft integration. We established optimal conditioning of the host brain environment to promote long-term survival and integration of grafted OLPs into an inflamed neonate host brain. Experimental procedures were performed under the United States Public Health Service Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care Committee at (UCLA) (ARC #1992-034-61) on July 1, 2010.

Genetic diversity of methicillin-resistant Staphylococcus aureus carrying type IV SCCmec in Orebro County and the western region of Sweden.

BACKGROUND: Recent studies have shown a predominance of type IV SCCmec among the methicillin-resistant Staphylococcus aureus (MRSA) isolated in the low endemic areas of Orebro County and the western region of Sweden. However, many of these isolates were not possible to classify as existing subtypes IVa, IVb, IVc or IVd. METHODS: We analysed 16 such MRSA isolates by multilocus sequence typing, spa typing, staphylocoagulase (SC) typing and detection of type IVg and IVh SCCmec. MRSA that remained as unknown type IV SCCmec were investigated by long-range PCR covering the J1 region; however, only two isolates were possible to amplify by PCR. The nucleotide sequences of the entire SCCmec of these two MRSA were determined. In addition, isolates that had unknown SC types were investigated by nucleotide sequencing of the coa genes. RESULTS: Five of 16 isolates were classified as type IVg SCCmec, and four isolates had type IVh SCCmec. Two subtypes of type IV SCCmec shared J1 regions previously identified in other types of SCCmec, types I.2 and II.2. The novel elements were designated as type IVi and IVj SCCmec. In addition, the genetic backgrounds of these Swedish MRSA were diverse and constituted at least nine sequence types and eight SC types, including four new types of SC. CONCLUSIONS: Type IV SCCmec is occurring in heterogeneous clones of MRSA in Sweden, and the majority of the type IV SCCmec were identified in community-acquired MRSA. We describe two novel subtypes of type IV SCCmec with common J1 regions shared by other types of SCCmec, which indicate that J1 regions occurred as primordial SCC.

Identification of nobiletin, a polymethoxyflavonoid, as an enhancer of adiponectin secretion.

Adiponectin, an adipocyte-derived protein with insulin-sensitizing, anti-diabetic and anti-atherogenic activities, is known to be induced during adipocyte differentiation. Nobiletin, a citrus polymethoxy flavonoid, was found to induce the differentiation of ST-13 preadipocytes into mature adipocytes and enhance the production of adiponectin protein at a concentration of 10 microM.

Novel type of staphylococcal cassette chromosome mec in a methicillin-resistant Staphylococcus aureus strain isolated in Sweden.

We identified a novel type of staphylococcal cassette chromosome mec (SCCmec) element carried by methicillin-resistant Staphylococcus aureus (MRSA) strain JCSC6082 isolated in Sweden. The SCCmec element was demarcated by characteristic nucleotide sequences at both ends and was integrated at the 3' end of orfX. The element carried a novel combination of a type 5 ccr gene complex and class C1 mec gene complex. The J regions of the element were homologous to those of the SCCmercury element of S. aureus strain 85/2082, with nucleotide identity greater than 99%. However, the novel SCCmec element from JCSC6082 did not carry the mer operon nor Tn554, suggesting that evolution to SCCmec could have been from a common ancestor by acquisition of the class C1 mec gene complex. The novel SCCmec element from JCSC6082 was flanked by a novel SCC-like chromosome cassette (CC6082), which was demarcated by two direct repeats and could be excised from the chromosome independently of the SCCmec element. Our data suggest that novel SCCmec elements can be generated on the staphylococcal chromosome through the recombination between extant SCC elements and mec gene complexes.

Combined genotoxic effects of radiation and a tobacco-specific nitrosamine in the lung of gpt delta transgenic mice.

It is important to evaluate the health effects of low-dose-rate or low-dose radiation in combination with chemicals as humans are exposed to a variety of chemical agents. Here, we examined combined genotoxic effects of low-dose-rate radiation and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the most carcinogenic tobacco-specific nitrosamine, in the lung of gpt delta transgenic mice. In this mouse model, base substitutions and deletions can be separately analyzed by gpt and Spi- selections, respectively. Female gpt delta mice were either treated with gamma-irradiation alone at a dose rate of 0.5, 1.0 or 1.5 mGy/h for 22 h/day for 31 days or combined with NNK treatments at a dose of 2 mg/mouse/day, i.p. for four consecutive days in the middle course of irradiation. In the gpt selection, the NNK treatments enhanced the mutation frequencies (MFs) significantly, but no obvious combined effects of gamma-irradiation were observable at any given radiation dose. In contrast, NNK treatments appeared to suppress the Spi- large deletions. In the Spi- selection, the MFs of deletions more than 1 kb in size increased in a dose-dependent manner. When NNK treatments were combined, the dose-response curve became bell-shaped where the MF at the highest radiation dose decreased substantially. These results suggest that NNK treatments may elicit an adaptive response that eliminates cells bearing radiation-induced double-strand breaks in DNA. Possible mechanisms underlying the combined genotoxicity of radiation and NNK are discussed, and the importance of evaluation of combined genotoxicity of more than one agent is emphasized.

Dormant Pluripotent Cells Emerge during Neural Differentiation of Embryonic Stem Cells in a FoxO3-Dependent Manner.

One major concern over the clinical application of embryonic stem cell (ESC)-derived cells is the potentiation of latent tumorigenicity by residual undifferentiated cells. Despite the use of intensive methodological approaches to eliminate residual undifferentiated cells, the properties of these cells remain elusive. Here, we show that under a serum-free neural differentiation condition, residual undifferentiated cells markedly delay progression of their cell cycle without compromising their pluripotency. This dormant pluripotency was maintained during reculture of the cells under a serum-free condition, whereas upon serum stimulation, the cells exited the dormant state and restarted proliferation and differentiation into all three germ layers. Microarray analysis revealed a set of genes that is significantly upregulated in the dormant ESCs compared with their levels of regulation in proliferating ESCs. Among them, we identified the transcription factor Forkhead box O3 (FoxO3) to be an essential regulator of the maintenance of pluripotency in dormant ESCs. Our study demonstrates that the transition into the dormant state endows residual undifferentiated cells with FoxO3-dependent and leukemia inhibitory factor/serum-independent pluripotency.

Utility of Genomic Assessment of Blood-Derived Circulating Tumor DNA (ctDNA) in Patients with Advanced Lung Adenocarcinoma.

Purpose: Genomic alterations in blood-derived circulating tumor DNA (ctDNA) from patients with non-small cell lung adenocarcinoma (NSCLC) were ascertained and correlated with clinical characteristics and therapeutic outcomes.Experimental Design: Comprehensive plasma ctDNA testing was performed in 88 consecutive patients; 34 also had tissue next-generation sequencing; 29, other forms of genotyping; and 25 (28.4%) had no tissue molecular tests because of inadequate tissue or biopsy contraindications.Results: Seventy-two patients (82%) had ≥1 ctDNA alteration(s); among these, 75% carried alteration(s) potentially actionable by FDA-approved (61.1%) or experimental drug(s) in clinical trials (additional 13.9%). The most frequent alterations were in the TP53 (44.3% of patients), EGFR (27.3%), MET (14.8%), KRAS (13.6%), and ALK (6.8%) genes. The concordance rate for EGFR alterations was 80.8% (100% vs. 61.5%; ≤1 vs. >1 month between ctDNA and tissue tests; P = 0.04) for patients with any detectable ctDNA alterations. Twenty-five patients (28.4%) received therapy matching ≥1 ctDNA alteration(s); 72.3% (N = 16/22) of the evaluable matched patients achieved stable disease ≥6 months (SD) or partial response (PR). Five patients with ctDNA-detected EGFR T790M were subsequently treated with a third generation EGFR inhibitor; all five achieved SD ≥ 6 months/PR. Patients with ≥1 alteration with ≥5% variant allele fraction (vs. < 5%) had a significantly shorter median survival (P = 0.012).Conclusions: ctDNA analysis detected alterations in the majority of patients, with potentially targetable aberrations found at expected frequencies. Therapy matched to ctDNA alterations demonstrated appreciable therapeutic efficacy, suggesting clinical utility that warrants future prospective studies. Clin Cancer Res; 23(17); 5101-11. ©2017 AACR.

Use of Liquid Biopsies in Clinical Oncology: Pilot Experience in 168 Patients.

PURPOSE: There is a growing interest in using circulating tumor DNA (ctDNA) testing in patients with cancer. EXPERIMENTAL DESIGN: A total of 168 patients with diverse cancers were analyzed. Patients had digital next-generation sequencing (54 cancer-related gene panel including amplifications in ERBB2, EGFR, and MET) performed on their plasma. Type of genomic alterations, potential actionability, concordance with tissue testing, and patient outcome were examined. RESULTS: Fifty-eight percent of patients (98/168) had ≥1 ctDNA alteration(s). Of the 98 patients with alterations, 71.4% had ≥ 1 alteration potentially actionable by an FDA-approved drug. The median time interval between the tissue biopsy and the blood draw was 2.7 months for patients with ≥ 1 alteration in common compared with 14.4 months (P = 0.006) for the patients in whom no common alterations were identified in the tissue and plasma. Overall concordance rates for tissue and ctDNA were 70.3% for TP53 and EGFR, 88.1% for PIK3CA, and 93.1% for ERBB2 alterations. There was a significant correlation between the cases with ≥ 1 alteration with ctDNA ≥ 5% and shorter survival (median = 4.03 months vs. not reached at median follow-up of 6.1 months; P < 0.001). Finally, 5 of the 12 evaluable patients (42%) matched to a treatment targeting an alteration(s) detected in their ctDNA test achieved stable disease ≥ 6 months/partial remission compared with 2 of 28 patients (7.1%) for the unmatched patients, P = 0.02. CONCLUSIONS: Our initial study demonstrates that ctDNA tests provide information complementary to that in tissue biopsies and may be useful in determining prognosis and treatment. Clin Cancer Res; 22(22); 5497-505. ©2016 AACR.

Autophagy linked FYVE (Alfy/WDFY3) is required for establishing neuronal connectivity in the mammalian brain.

The regulation of protein degradation is essential for maintaining the appropriate environment to coordinate complex cell signaling events and to promote cellular remodeling. The Autophagy linked FYVE protein (Alfy), previously identified as a molecular scaffold between the ubiquitinated cargo and the autophagic machinery, is highly expressed in the developing central nervous system, indicating that this pathway may have yet unexplored roles in neurodevelopment. To examine this possibility, we used mouse genetics to eliminate Alfy expression. We report that this evolutionarily conserved protein is required for the formation of axonal tracts throughout the brain and spinal cord, including the formation of the major forebrain commissures. Consistent with a phenotype reflecting a failure in axon guidance, the loss of Alfy in mice disrupts localization of glial guidepost cells, and attenuates axon outgrowth in response to Netrin-1. These findings further support the growing indication that macroautophagy plays a key role in the developing CNS.

Low dose of wortmannin reduces radiosensitivity of human glioblastoma cells through the p53 pathway.

Wortmannin is an inhibitor of PI3-kinase and acts on cultured cells at dosages below 1 microM. Wortmannin also inhibits the gene products of the PI3-kinase family such as ATM or DNA-PK at dosages above 10 microM in cultured cells. There are many reports on the enhancement of radiosensitivity by a high dose of wortmannin inhibiting the proteins of the PI3-kinase family. However, there have been no reports on the effect on radiosensitivity of low doses of wortmannin inhibiting PI3-kinase. We found that low doses of wortmannin reduced the radiosensitivity of human A172 glioblastoma cells. This effect was shown only in wild-type p53 cells, but was not shown in mutant p53 cells such as T98G or A172/248W carrying a dominant point-mutated p53 gene. This result indicates that the PI3-kinase, or another wortmannin-sensitive enzyme, may affect the signal transduction of p53. We examined the response of the p53 pathway by X-ray irradiation. A low dose of wortmannin did not affect the accumulation of p53 and the phosphorylation of p53 at ser-15, but reduced the induction of WAF1 and enhanced the induction of GADD45.