The tumor suppressor p53 and its close relative p73 are activated in response to DNA damage resulting in either cell cycle arrest or apoptosis. Here, we show that DNA damage induces the acetylation of p73 by the acetyltransferase p300. Inhibiting the enzymatic activity of p300 hampers apoptosis in a p53(-/-) background. Furthermore, a nonacetylatable p73 is defective in activating transcription of the proapoptotic p53AIP1 gene but retains an intact ability to regulate other targets such as p21. Finally, p300-mediated acetylation of p73 requires the protooncogene c-abl. Our results suggest that DNA damage-induced acetylation potentiates the apoptotic function of p73 by enhancing the ability of p73 to selectively activate the transcription of proapoptotic target genes.
Summary Autophagy degrades lipid droplets (LD) via lipophagy. Cytosolic lipases, ATGL and HSL, are canonical mechanisms for lipolysis. Whether autophagy proteins engage in direct crosstalk with lipases to promote lipid mobilization remains unknown. The integrative physiology of an inter-organ communication in lipophagy regulation is also unknown. Here, we show that cold induces autophagy in proopiomelanocortin (POMC) neurons, and activates lipophagy in brown fat (BAT) and liver in mice. Targeted activation of autophagy in POMC neurons via intra-hypothalamic rapamycin is sufficient to trigger lipid utilization in room temperature-housed mice. Conversely, inhibiting autophagy in POMC neurons or in peripheral tissues or denervating BAT blocks lipid utilization. Unexpectedly, the autophagosome marker LC3 is mechanistically coupled to ATGL-mediated lipolysis. ATGL exhibits LC3-interacting region (LIR) motifs, and mutating a single LIR motif on ATGL displaces ATGL from LD and disrupts lipolysis. Thus, autophagy in the CNS and periphery coordinate lipophagy in the control of lipolysis.
Automatic acquisition of lexical knowledge is critical to a wide range of natural language processing tasks. Especially important is knowledge about verbs, which are the primary source of relational information in a sentence-the predicate-argument structure that relates an action or state to its participants (i.e., who did what to whom). In this work, we report on supervised learning experiments to automatically classify three major types of English verbs, based on their argument structure-specifically, the thematic roles they assign to participants. We use linguistically-motivated statistical indicators extracted from large annotated corpora to train the classifier, achieving 69.8% accuracy for a task whose baseline is 34%, and whose expert-based upper bound we calculate at 86.5%. A detailed analysis of the performance of the algorithm and of its errors confirms that the proposed features capture properties related to the argument structure of the verbs. Our results validate our hypotheses that knowledge about thematic relations is crucial for verb classification, and that it can be gleaned from a corpus by automatic means. We thus demonstrate an effective combination of deeper linguistic knowledge with the robustness and scalability of statistical techniques.
The protein kinase mammalian Sterile 20-like kinase 1 (MST1) plays a critical role in the regulation of cell death. Recent studies suggest that MST1 mediates oxidative stress-induced neuronal cell death by phosphorylating the transcription factor FOXO3 at serine 207, a site that is conserved in other FOXO family members. Here, we show that MST1-induced phosphorylation of FOXO1 at serine 212, corresponding to serine 207 in FOXO3, disrupts the association of FOXO1 with 14-3-3 proteins. Accordingly, MST1 mediates the nuclear translocation of FOXO1 in primary rat cerebellar granule neurons that are deprived of neuronal activity. We also find a requirement for MST1 in cell death of granule neurons upon withdrawal of growth factors and neuronal activity, and MST1 induces cell death in a FOXO1-dependent manner. Finally, we show that the MST1-regulatory, scaffold protein Nore1 is required for survival factor deprivation induced neuronal death. Collectively, these findings define MST1-FOXO1 signaling as an important link survival factor deprivation-induced neuronal cell death with implications for our understanding of brain development and neurological diseases.During normal development, neurons die by the process of apoptosis to ensure the proper wiring of the nervous system (1, 2). In the mature nervous system, aberrant neuronal cell death contributes to the pathogenesis of a large number of diseases (3-5). Therefore, elucidation of the molecular underpinnings of neuronal cell death is essential for our understanding of brain development and also offers the possibility of identification of targets for the development of drugs that prevent neuronal degeneration in brain diseases.Granule neurons of the rat cerebellum provide a robust system for the study of the mechanisms that govern neuronal cell death (6, 7). The survival of cerebellar granule neurons during normal development is promoted by growth factors and neuronal activity (8 -12). Likewise, the survival of primary rat cerebellar granule neurons is supported by polypeptide growth factors, provided by serum and neuronal activity, and mimicked by the activation of voltage-sensitive calcium channels induced by membrane depolarization (13-15). Granule neurons have also proved useful in the study of mechanisms of neuronal cell death in response to pathologically relevant stimuli such as oxidative stress (16).The protein kinase mammalian Sterile 20-like kinase 1 (MST1) 5 has been implicated in the control of neuronal cell death (16,17). Exposure of rat cerebellar granule neurons to hydrogen peroxide leads to MST1-dependent cell death (16). Oxidative stress-induced MST1 triggers neuronal cell death via the transcription factor FOXO3. MST1 catalyzes the phosphorylation of FOXO3 at serine 207, a site that lies within its forkhead domain, and thereby promotes the dissociation of FOXO3 from 14-3-3 proteins. The 14-3-3 proteins sequester FOXO3 in the cytoplasm and thus inhibit FOXO3-dependent transcription and cell death. The consequence of the MST1-induced phosphorylation of...
Activation of cyclin-dependent kinase 1 (Cdk1) has been linked to cell death of postmitotic neurons in brain development and disease. We found that Cdk1 phosphorylated the transcription factor FOXO1 at Ser249 in vitro and in vivo. The phosphorylation of FOXO1 at Ser249 disrupted FOXO1 binding with 14-3-3 proteins and thereby promoted the nuclear accumulation of FOXO1 and stimulated FOXO1-dependent transcription, leading to cell death in neurons. In proliferating cells, Cdk1 induced FOXO1 Ser249 phosphorylation at the G2/M phase of the cell cycle, resulting in FOXO1-dependent expression of the mitotic regulator Polo-like kinase (Plk). These findings define a conserved signaling link between Cdk1 and FOXO1 that may have a key role in diverse biological processes, including the degeneration of postmitotic neurons.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.