Biomedical subjects

Masako Narita

Publications and source records attributed to Masako Narita.

7 recordsLinked to original sources

PubMed2006

A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation.

Cellular senescence is a stable state of proliferative arrest that provides a barrier to malignant transformation and contributes to the antitumor activity of certain chemotherapies. Senescent cells can accumulate senescence-associated heterochromatic foci (SAHFs), which may provide a chromatin buffer that prevents activation of proliferation-associated genes by mitogenic transcription factors. Surprisingly, we show that the High-Mobility Group A (HMGA) proteins, which can promote tumorigenesis, accumulate on the chromatin of senescent fibroblasts and are essential structural components of SAHFs. HMGA proteins cooperate with the p16(INK4a) tumor suppressor to promote SAHF formation and proliferative arrest and stabilize senescence by contributing to the repression of proliferation-associated genes. These antiproliferative activities are canceled by coexpression of the HDM2 and CDK4 oncogenes, which are often coamplified with HMGA2 in human cancers. Our results identify a component of the senescence machinery that contributes to heterochromatin formation and imply that HMGA proteins also act in tumor suppressor networks.

Animals↗

PubMed2005

p400 is required for E1A to promote apoptosis.

The adenovirus E1A oncoprotein promotes proliferation and transformation by binding cellular proteins, including members of the retinoblastoma protein family, the p300/CREB-binding protein transcriptional coactivators, and the p400-TRRAP chromatin-remodeling complex. E1A also promotes apoptosis, in part, by engaging the ARF-p53 tumor suppressor pathway. We show that E1A induces ARF and p53 and promotes apoptosis in normal fibroblasts by physically associating with the retinoblastoma protein and a p400-TRRAP complex and that its interaction with p300 is largely dispensable for these effects. We further show that E1A increases p400 expression and, conversely, that suppression of p400 using stable RNA interference reduces the levels of ARF, p53, and apoptosis in E1A-expressing cells. Therefore, whereas E1A inactivates the retinoblastoma protein, it requires p400 to efficiently promote cell death. These results identify p400 as a regulator of the ARF-p53 pathway and a component of the cellular machinery that couples proliferation to cell death.

ADP-Ribosylation Factors↗

PubMed2005

The p400 E1A-associated protein is a novel component of the p53 --> p21 senescence pathway.

Adenovirus E1A-associated p400 belongs to the SWI2/SNF2 family of chromatin remodeling proteins. Here, we report that p400 is a component of the p53-p21(WAF1/CIP1/sid1) pathway, regulating the p21 transcription and senescence induction program. Acute depletion of p400 expression by shRNA (short hairpin RNA) synthesis led to premature senescence of untransformed human fibroblasts, whose features include G1 arrest, p21 induction, senescence-associated heterochromatic foci (SAHF), and beta-gal staining. Importantly, p400shRNA-induced premature senescence phenotypes were rescued by coexpression of p53-shRNA or p21-shRNA. Furthermore, p400 complex colocalized with p53 on the p21 promoter. These data suggest that the p400 complex inhibits p53 --> p21 transcription and the development of premature senescence.

Cell Cycle Proteins↗

PubMed2004

PML is a direct p53 target that modulates p53 effector functions.

The p53 tumor suppressor promotes cell cycle arrest or apoptosis in response to stress. Previous work suggests that the promyelocytic leukemia gene (PML) can act upstream of p53 to enhance transcription of p53 targets by recruiting p53 to nuclear bodies (NBs). We show that PML is itself a p53 target gene that also acts downstream of p53 to potentiate its antiproliferative effects. Hence, p53 is required for PML induction in response to oncogenes and DNA damaging chemotherapeutics. Furthermore, the PML gene contains p53 binding sites that confer p53 responsiveness to a heterologous reporter and can bind p53 in vitro and in vivo. Finally, cells lacking PML show a reduced propensity to undergo senescence or apoptosis in response to p53 activation, despite the induction of several p53 target genes. These results identify an additional element of PML regulation and establish PML as a mediator of p53 tumor suppressor functions.

Animals↗

PubMed2003

Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence.

Cellular senescence is an extremely stable form of cell cycle arrest that limits the proliferation of damaged cells and may act as a natural barrier to cancer progression. In this study, we describe a distinct heterochromatic structure that accumulates in senescent human fibroblasts, which we designated senescence-associated heterochromatic foci (SAHF). SAHF formation coincides with the recruitment of heterochromatin proteins and the retinoblastoma (Rb) tumor suppressor to E2F-responsive promoters and is associated with the stable repression of E2F target genes. Notably, both SAHF formation and the silencing of E2F target genes depend on the integrity of the Rb pathway and do not occur in reversibly arrested cells. These results provide a molecular explanation for the stability of the senescent state, as well as new insights into the action of Rb as a tumor suppressor.

Binding Sites↗

PubMed2003

Effects of aldehyde dehydrogenase genotypes on carotid atherosclerosis.

Atherosclerotic diseases are thought to be less frequent in Asians compared with Caucasians. Unlike Caucasians, nearly half of Asians have a functional deficiency in the low Km aldehyde dehydrogenase (ALDH2), a key enzyme in alcohol metabolism, which potentially modifies the prevalence of atherosclerosis. This study examined the associations between ALDH2 genotypes ("typical homo," "hetero" or "atypical homo") and carotid atherosclerosis in 304 Japanese patients. As a measure of carotid atherosclerosis, plaque score (PS) was evaluated by B-mode ultrasonography. Age- and sex-adjusted PS was lower in "atypical homo" genotype patients (2.7 +/- 1.2 [mean +/- standard error], n=21) (p<0.05) and tended to be lower in "hetero" patients (4.5 +/- 0.5, n=116) (p=0.07) compared with "typical homo" patients (5.7 +/- 0.4, n=167). When we controlled for traditional cardiovascular risk factors and alcohol intake, the "atypical homo" genotype was found to be associated with lower PS (beta=-0.13, p<0.05). Based on these findings, the ALDH2 genotypes seem to be associated with the severity of carotid atherosclerosis, potentially modifying the prevalence of atherosclerosis in Asians.

Aged↗

PubMed2003

Carotid atherosclerosis as a risk factor for complex aortic lesions in patients with ischemic cerebrovascular disease.

Aortic arch atherosclerotic lesions can cause ischemic cerebrovascular disease (ICVD). The association between carotid and aortic atherosclerosis was examined, and it was investigated whether noninvasive carotid evaluation aids in the identification of aortic lesions as potential ICVD risk. The subjects comprised 147 patients with ICVD who had undergone carotid ultrasonography and transesophageal echocardiography. Carotid and aortic arch atherosclerosis was evaluated by measuring the maximum intima - media thickness (IMT), with aortic IMT of at least 4 mm, mobile plaques and/or ulcers defined as complex aortic lesions with potential ICVD risk. Carotid IMT was linearly associated with aortic IMT (r=0.53, p<0.001), and the association was independent of traditional cardiovascular risk factors (beta =0.36, p<0.001). Also, each 1 SD greater carotid IMT was associated with 4.2-fold (95% confidence interval: 2.5-7.0) higher likelihood of complex aortic lesions, with the likelihood little modified when controlling for cardiovascular risk factors. In particular, complex aortic lesions were found in 78% of patients with the highest carotid IMT tertile, compared with 14% of those with the lowest tertile (p<0.05). Based on these findings, carotid atherosclerosis is associated with aortic atherosclerosis, representing a risk factor for aortic lesions that are a potential ICVD risk.

Aged↗