Oncogenes and senescence: breaking down in the fast lane.
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Animals↗
Biomedical subjects
Masashi Narita
Publications and source records attributed to Masashi Narita.
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↗
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↗
Prevalence of venous thromboembolism at a teaching hospital in Okinawa, Japan.
Limited data suggest that Asian Americans may have a lower risk of venous thromboembolism (VTE) than Caucasians. However, the actual prevalence of VTE among Asians remains controversial, and has not been described in Japan. We studied all 131,060 patients hospitalized at a single medical centre in Japan (January 1987 - December 1999). Patients with VTE were identified through discharge diagnoses. Hospital records were reviewed for information on patient demographics, risk factors, and diagnostic modalities. VTE occurred in 0.11% of admissions (n=141, 95%CI 0.09-0.13%). Mean age (+/-SD) was 64+/-17 years, 70% were women, 91% had deep vein thrombosis, and 29% pulmonary embolism. Among hospitalized patients 50-69 years old, VTE was significantly more common among women than men (0.31% vs. 0.08%; OR 3.88; 95%CI 1.45-6.31). We found a low prevalence of VTE in Japan compared to that reported in the US. Future studies are needed to clarify the reasons for our findings.
Adult↗
Leptospirosis after recreational exposure to water in the Yaeyama islands, Japan.
Leptospirosis is a global zoonotic disease with a variety of clinical manifestations. We report an outbreak of leptospirosis in the Yaeyama Islands, Japan, in the summer of 1999 associated with heavy rainfall. Fourteen people were diagnosed with leptospirosis and required hospitalization. All cases were found to have exposure to contaminated soil or water. A history of recreational activities involving water sports was more frequent (71%) than occupational risk factors related to agriculture or construction (29%). Fever was the primary symptom in all cases, followed by chills (93%), headache (86%), myalgias (57%) and conjunctival suffusion (57%). All cases were successfully treated with antimicrobial therapy except one patient who improved spontaneously. Jarisch-Herxheimer reactions were seen in six cases (43%). The increasing incidence of leptospirosis related to recreational sports is an important public health problem in resort areas. A high-index of suspicion, early treatment, and prevention are crucial in this latently endemic area.
Adolescent↗
Executing cell senescence.
Senescence is a permanent form of cell cycle arrest that limits the proliferation of damaged cells and may contribute to tumor suppression and aging. We recently demonstrated that some senescent cell types undergo dramatic changes in chromatin organization that are dependent on the retinoblastoma protein and are associated with the stable repression of some E2F target genes. Here we show how these changes might contribute to the stability of the senescent state.
Animals↗
Simulation of characteristics of a LiNbO3/diamond surface acoustic wave.
High-frequency surface acoustic wave (SAW) devices based on diamond that have been produced to date utilize the SiO2/ZnO/diamond structure, which shows excellent characteristics of a phase velocity of over 10,000 m/s with a zero temperature coefficient; this structure has been successfully applied to high-frequency narrowband filters and resonators. To expand material systems to wideband applications, c-axis-oriented LiNbO3 on diamond was studied and a coupling coefficient up to 9.0% was estimated to be obtained. In this paper, the characteristics of LiNbO3/diamond with the assumption that the LiNbO3 film is a single crystal have been studied by theoretical calculations to find higher coupling coefficient conditions. Calculations are made for the phase velocity, the coupling coefficient, and the temperature coefficient of the Rayleigh wave and its higher mode Sezawa waves. As a result, LiNbO3/diamond is found to offer a very high electromechanical coupling coefficient of up to 16% in conjunction with a high phase velocity of 12,600 m/s and a small temperature coefficient of 25 ppm/deg. This characteristic is suitable for wide bandwidth applications in high-frequency SAW devices.
Journal Article↗
Reversal of human cellular senescence: roles of the p53 and p16 pathways.
Telomere erosion and subsequent dysfunction limits the proliferation of normal human cells by a process termed replicative senescence. Replicative senescence is thought to suppress tumorigenesis by establishing an essentially irreversible growth arrest that requires activities of the p53 and pRB tumor suppressor proteins. We show that, depending on expression of the pRB regulator p16, replicative senescence is not necessarily irreversible. We used lentiviruses to express specific viral and cellular proteins in senescent human fibroblasts and mammary epithelial cells. Expression of telomerase did not reverse the senescence arrest. However, cells with low levels of p16 at senescence resumed robust growth upon p53 inactivation, and limited growth upon expression of oncogenic RAS. In contrast, cells with high levels of p16 at senescence failed to proliferate upon p53 inactivation or RAS expression, although they re-entered the cell cycle without growth after pRB inactivation. Our results indicate that the senescence response to telomere dysfunction is reversible and is maintained primarily by p53. However, p16 provides a dominant second barrier to the unlimited growth of human cells.
Breast↗
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↗
14-3-3 Interacts directly with and negatively regulates pro-apoptotic Bax.
The Bcl-2 family of proteins comprises well characterized regulators of apoptosis, consisting of anti-apoptotic members and pro-apoptotic members. Pro-apoptotic members possessing BH1, BH2, and BH3 domains (such as Bax and Bak) act as a gateway for a variety of apoptotic signals. Bax is normally localized to the cytoplasm in an inactive form. In response to apoptotic stimuli, Bax translocates to the mitochondria and undergoes oligomerization to induce the release of apoptogenic factors such as cytochrome c, but it is still largely unknown how the mitochondrial translocation and pro-apoptotic activity of Bax is regulated. Here we report that cytoplasmic protein 14-3-3 theta binds to Bax and, upon apoptotic stimulation, releases Bax by a caspase-independent mechanism, as well as through direct cleavage of 14-3-3 theta by caspases. Unlike Bad, the interaction with 14-3-3 theta is not dependent on the phosphorylation of Bax. In isolated mitochondria, we found that 14-3-3 theta inhibited the integration of Bax and Bax-induced cytochrome c release. Bax-induced apoptosis was inhibited by overexpression of either 14-3-3 theta or its mutant (which lacked the ability to bind to various phosphorylated targets but still bound to Bax), whereas overexpression of 14-3-3 theta was unable to inhibit apoptosis induced by a Bax mutant that did not bind to 14-3-3 theta. These findings indicate that 14-3-3 theta plays a crucial role in negatively regulating the activity of Bax.
14-3-3 Proteins↗
Direct coupling of the cell cycle and cell death machinery by E2F.
Unrestrained E2F activity forces S phase entry and promotes apoptosis through p53-dependent and -independent mechanisms. Here, we show that deregulation of E2F by adenovirus E1A, loss of Rb or enforced E2F-1 expression results in the accumulation of caspase proenzymes through a direct transcriptional mechanism. Increased caspase levels seem to potentiate cell death in the presence of p53-generated signals that trigger caspase activation. Our results demonstrate that mitogenic oncogenes engage a tumour suppressor network that functions at multiple levels to efficiently induce cell death. The data also underscore how cell cycle progression can be coupled to the apoptotic machinery.
Adenovirus E1A Proteins↗