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An apoptotic signaling pathway in the interferon antiviral response mediated by RNase L and c-Jun NH2-terminal kinase 总被引:5,自引:0,他引:5
Cellular stress responses induced during viral infections are critical to the health and survival of organisms. In higher vertebrates, interferons (IFNs) mediate the innate antiviral response in part through the action of RNase L, a uniquely regulated enzyme. RNase L is activated by 5'-phosphorylated, 2'-5' oligoadenylates (2-5A) produced from IFN-inducible and double stranded RNA-dependent synthetases. We show that viral activation of the c-Jun NH2-terminal kinases (JNK) family of MAP kinases and viral induction of apoptosis are both deficient in mouse cells lacking RNase L. Also, JNK phosphorylation in response to 2-5A was greatly reduced in RNase L-/- mouse cells. In addition, 2-5A treatment of the human ovarian carcinoma cell line, Hey1b, resulted in specific ribosomal RNA cleavage products coinciding with JNK activation. Furthermore, suppression of JNK activity with the chemical inhibitor, SP600125, prevented apoptosis induced by 2-5A. In contrast, inhibition of alternative MAP kinases, p38 and ERK, failed to prevent 2-5A-mediated apoptosis. Short interfering RNA to JNK1/JNK2 mRNAs resulted in JNK ablation while also suppressing 2-5A-mediated apoptosis. Moreover, Jnk1-/- Jnk2-/- cells were highly resistant to the apoptotic effects of IFN and 2-5A. These findings suggest that JNK and RNase L function in an integrated signaling pathway during the IFN response that leads to elimination of virus-infected cells through apoptosis. 相似文献
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Toh WH Siddique MM Boominathan L Lin KW Sabapathy K 《The Journal of biological chemistry》2004,279(43):44713-44722
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Misato Hayashi Fumito Kawakami Rosimah Roslan Nurhafizie M. Hapiszudin Sabapathy Dharmalingam 《Primates; journal of primatology》2018,59(2):135-144
The Bukit Merah Orang Utan Island (OUI) Foundation has been conducting behavioral and veterinary research on orangutans as an attempt at ex situ conservation. Since 2010, the Primate Research Institute, Kyoto University has been collaborating with OUI to promote environmental enrichment and infant rearing by biological mothers in addition to the continuous efforts of refining the veterinary management of the endangered species. In 2011, three Bornean orangutans (Pongo pygmaeus pygmaeus) were released on an island, called BJ Island, adjacent to OUI. This island is approximately 5.6 ha in size, and 635 trees belonging to 102 plant species were identified prior to their release. Behavioral monitoring of the released individuals has been conducted to evaluate their behavioral adaptation to the new environment. Two of the three released orangutans were born in the wild, whereas the youngest individual was born on OUI and expected to learn forest survival strategies from the two older individuals. One of the orangutans was pregnant at the time of release and subsequently gave birth to two male infants on BJ Island. The behavioral monitoring indicated that these orangutans traveled more and spent more time on trees following their release onto BJ Island. However, resting was longer for two females both on OUI and BJ Island when compared to other populations. The orangutans consumed some natural food resources on BJ Island. The release into a more naturalistic environment may help the orangutans to develop more naturalistic behavioral patterns that resemble their wild counterparts. 相似文献
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Kanaga Sabapathy 《Molecular and cellular biology》2016,36(6):848-854
The role of p73, the homologue of the tumor suppressor p53, in regulating angiogenesis has recently been extensively investigated, resulting in the publication of five articles. Of these, two studies suggested a suppressive role, while the others implied a stimulatory role for the p73 isoforms in regulating angiogenesis. A negative role for TAp73, the full-length form that is often associated with tumor suppression, in blood vessel formation, is consistent with its general attributes and was proposed to be effected indirectly through the degradation of hypoxia-inducible factor 1α (HIF1-α), the master angiogenic regulator. In contrast, a positive role for TAp73 coincides with its recently understood role in supporting cellular survival and thus tumorigenesis, consistent with TAp73 being not-mutated but rather often overexpressed in clinical contexts. In the latter case, TAp73 expression was induced by hypoxia via HIF1-α, and it appears to directly promote angiogenic target gene activation and blood vessel formation independent of HIF1-α. This mini review will provide an overview of these seemingly opposite recent findings as well as earlier data, which collectively establish the definite possibility that TAp73 is indeed capable of both promoting and inhibiting angiogenesis, depending on the cellular context. 相似文献
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Cellular stimulation results in phosphorylation of the tumor suppressor p53 on multiple residues, though the functional relevance is not always clear. It is noteworthy that the serine (S) 315 residue is unique, as it has been suggested to be phosphorylated not only by genotoxic signals, but also during cell-cycle progression and by endoplasmic-reticulum stress. However, in vitro data have been conflicting as phosphorylation at this site was shown to both positively and negatively regulate p53 functions. We have thus generated knock-in mice expressing an unphosphorylable S312 (equivalent to human S315), by substitution with an alanine (A) residue, to clarify the conflicting observations and to evaluate its functional relevance in vivo. Born at Mendelian ratios, the p53S312A/S312A mice show no anomalies during development and adulthood. p53 activation, stability, localization and ability to induce apoptosis, cell-cycle arrest and prevent centrosome amplification are not compromised in p53S312A/S312A cells. p53S312A/S312A mice are unable to rescue mdm2−/− lethality, and tumorigenesis – both spontaneous and irradiation/oncogene-induced – is not accentuated. Taken together, the results show that the S312 phosphorylation site is not in itself necessary for efficient p53 function, and advocates the possibility that it is neither relevant in the mouse context nor important for p53 functions in vivo. 相似文献