Cell Death and Differentiation最新文献

{"title":"Apoptosis signaling is activated as a transient pulse in neurons","authors":"Keeley L. Spiess, Matthew J. Geden, Selena E. Romero, Emilie Hollville, Elizabeth S. Hammond, Rachel L. Patterson, Quintin B. Girardi, Mohanish Deshmukh","doi":"10.1038/s41418-024-01403-5","DOIUrl":"https://doi.org/10.1038/s41418-024-01403-5","url":null,"abstract":"<p>Apoptosis is a fundamental process of all mammalian cells but exactly how it is regulated in different primary cells remains less explored. In most contexts, apoptosis is engaged to eliminate cells. However, postmitotic cells such as neurons must efficiently balance the need for developmental apoptosis <i>versus</i> the physiological needs for their long-term survival. Neurons are capable of reversing the commitment to death even after the point of cytochrome <i>c</i> release. This ability of neurons to recover from an apoptotic signal suggests that activation of the apoptotic pathway in neurons could be much more transient than is currently recognized. Here, we investigated whether the apoptotic pathway in neurons is a persistent signal or a transient pulse in continuous presence of apoptotic stimulus. We have examined this at three key steps in apoptotic signaling: phosphorylation of c-Jun, induction of the BH3-only family proteins and Bax activation. Strikingly, we found all three of these events occur as transient signals following Nerve Growth Factor (NGF) deprivation-induced apoptosis in sympathetic neurons. This transient apoptosis signal would effectively allow neurons to reset and permit recovery if the apoptotic stimulus is reversed. Excitingly, we have also discovered that a neuron’s ability to recover from an apoptotic signal is dependent on expression of the anti-apoptotic Bcl-2 family protein Bcl-xL. Bcl-xL-deficient neurons lose the ability to recover from NGF deprivation even if NGF is restored. Additionally, we show that recovery from a previous exposure to NGF deprivation is protective against subsequent deprivation. Together, these results define a novel mechanism by which apoptosis is regulated in neurons where the transient pulse of the apoptotic signaling supports neuronal resilience.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"25 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RIP1 inhibition protects retinal ganglion cells in glaucoma models of ocular injury","authors":"Bo Kyoung Kim, Tatiana Goncharov, Sébastien A. Archaimbault, Filip Roudnicky, Joshua D. Webster, Peter D. Westenskow, Domagoj Vucic","doi":"10.1038/s41418-024-01390-7","DOIUrl":"https://doi.org/10.1038/s41418-024-01390-7","url":null,"abstract":"<p>Receptor-interacting protein 1 (RIP1, RIPK1) is a critical mediator of multiple signaling pathways that promote inflammatory responses and cell death. The kinase activity of RIP1 contributes to the pathogenesis of a number of inflammatory and neurodegenerative diseases. However, the role of RIP1 in retinopathies remains unclear. This study demonstrates that RIP1 inhibition protects retinal ganglion cells (RGCs) in preclinical glaucoma models. Genetic inactivation of RIP1 improves RGC survival and preserves retinal function in the preclinical glaucoma models of optic nerve crush (ONC) and ischemia–reperfusion injury (IRI). In addition, the involvement of necroptosis in ONC and IRI glaucoma models was examined by utilizing RIP1 kinase-dead (RIP1-KD), RIP3 knockout (RIP3-KO), and MLKL knockout (MLKL-KO) mice. The number of RGCs, retinal thickness, and visual acuity were rescued in RIP1-kinase-dead (RIP1-KD) mice in both models, while wild-type (WT) mice experienced significant retinal thinning, RGC loss, and vision impairment. RIP3-KO and MLKL-KO mice showed moderate protective effects in the IRI model and limited in the ONC model. Furthermore, we confirmed that a glaucoma causative mutation in optineurin, OPTN-E50K, sensitizes cells to RIP1-mediated inflammatory cell death. RIP1 inhibition reduces RGC death and axonal degeneration following IRI in mice expressing OPTN-WT and OPTN-E50K variant mice. We demonstrate that RIP1 inactivation suppressed microglial infiltration in the RGC layer following glaucomatous damage. Finally, this study highlights that human glaucomatous retinas exhibit elevated levels of <i>TNF</i> and <i>RIP3</i> mRNA and microglia infiltration, thus demonstrating the role of neuroinflammation in glaucoma pathogenesis. Altogether, these data indicate that RIP1 plays an important role in modulating neuroinflammation and that inhibiting RIP1 activity may provide a neuroprotective therapy for glaucoma.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"17 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TP53: the unluckiest of genes?","authors":"Andreas C. Joerger, Thorsten Stiewe, Thierry Soussi","doi":"10.1038/s41418-024-01391-6","DOIUrl":"https://doi.org/10.1038/s41418-024-01391-6","url":null,"abstract":"<p>The transcription factor p53 plays a key role in the cellular defense against cancer development. It is inactivated in virtually every tumor, and in every second tumor this inactivation is due to a mutation in the <i>TP53</i> gene. In this perspective, we show that this diverse mutational spectrum is unique among all other cancer-associated proteins and discuss what drives the selection of <i>TP53</i> mutations in cancer. We highlight that several factors conspire to make the p53 protein particularly vulnerable to inactivation by the mutations that constantly plague our genome. It appears that the <i>TP53</i> gene has emerged as a victim of its own evolutionary past that shaped its structure and function towards a pluripotent tumor suppressor, but came with an increased structural fragility of its DNA-binding domain. <i>TP53</i> loss of function - with associated dominant-negative effects - is the main mechanism that will impair <i>TP53</i> tumor suppressive function, regardless of whether a neomorphic phenotype is associated with some of these variants.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"210 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oncometabolites at the crossroads of genetic, epigenetic and ecological alterations in cancer","authors":"Letizia Lanzetti","doi":"10.1038/s41418-024-01402-6","DOIUrl":"10.1038/s41418-024-01402-6","url":null,"abstract":"By the time a tumor reaches clinical detectability, it contains around 108–109 cells. However, during tumor formation, significant cell loss occurs due to cell death. In some estimates, it could take up to a thousand cell generations, over a ~ 20-year life-span of a tumor, to reach clinical detectability, which would correspond to a “theoretical” generation of ~1030 cells. These rough calculations indicate that cancers are under negative selection. The fact that they thrive implies that they “evolve”, and that their evolutionary trajectories are shaped by the pressure of the environment. Evolvability of a cancer is a function of its heterogeneity, which could be at the genetic, epigenetic, and ecological/microenvironmental levels [1]. These principles were summarized in a proposed classification in which Evo (evolutionary) and Eco (ecological) indexes are used to label cancers&nbsp;[1]. The Evo index addresses cancer cell-autonomous heterogeneity (genetic/epigenetic). The Eco index describes the ecological landscape (non-cell-autonomous) in terms of hazards to cancer survival and resources available. The reciprocal influence of Evo and Eco components is critical, as it can trigger self-sustaining loops that shape cancer evolvability [2]. Among the various hallmarks of cancer [3], metabolic alterations appear unique in that they intersect with both Evo and Eco components. This is partly because altered metabolism leads to the accumulation of oncometabolites. These oncometabolites have traditionally been viewed as mediators of non-cell-autonomous alterations in the cancer microenvironment. However, they are now increasingly recognized as inducers of genetic and epigenetic modifications. Thus, oncometabolites are uniquely positioned at the crossroads of genetic, epigenetic and ecological alterations in cancer. In this review, the mechanisms of action of oncometabolites will be summarized, together with their roles in the Evo and Eco phenotypic components of cancer evolvability. An evolutionary perspective of the impact of oncometabolites on the natural history of cancer will be presented.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 12","pages":"1582-1594"},"PeriodicalIF":13.7,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41418-024-01402-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial Expression of Concern: The NAD+ salvage pathway modulates cancer cell viability via p73","authors":"T. Sharif,&nbsp;D.-G. Ahn,&nbsp;R.-Z. Liu,&nbsp;E. Pringle,&nbsp;E. Martell,&nbsp;C. Dai,&nbsp;A. Nunokawa,&nbsp;M. Kwak,&nbsp;D. Clements,&nbsp;J. P. Murphy,&nbsp;C. Dean,&nbsp;P. Marcato,&nbsp;C. McCormick,&nbsp;R. Godbout,&nbsp;S. A. Gujar,&nbsp;P. W. K. Lee","doi":"10.1038/s41418-024-01382-7","DOIUrl":"10.1038/s41418-024-01382-7","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 11","pages":"1577-1577"},"PeriodicalIF":13.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41418-024-01382-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myeloid Mir34a suppresses colitis-associated colon cancer: characterization of mediators by single-cell RNA sequencing","authors":"Janine König, Matjaz Rokavec, Meryem Gülfem Öner-Ziegler, Ye Fei, Heiko Hermeking","doi":"10.1038/s41418-024-01380-9","DOIUrl":"https://doi.org/10.1038/s41418-024-01380-9","url":null,"abstract":"<p>We have previously shown that general deletion of the gene encoding the p53-inducible Mir34a microRNA enhances the number and invasion of colitis-associated colorectal cancers (CACs) in mice. Since the p53-pathway has been implicated in tumor-suppression mediated by cells in the tumor microenvironment (TME) we deleted <i>Mir34a</i> in myeloid cells and characterized CACs in these with scRNA-Seq (single cell RNA sequencing). This revealed an increase in specific macrophage subtypes, such as <i>Cdk8</i>⁺ macrophages and <i>Mrc1</i>⁺, M2-like macrophages. The latter displayed elevated expression of 21 known Mir34a target mRNAs, including <i>Csf1r, Axl, Foxp1, Ccr1, Nampt, and Tgfbr2</i>, and 32 predicted Mir34a target mRNAs. Furthermore, <i>Mir34a</i>-deficient BMDMs showed enhanced migration, elevated expression of <i>Csf1r</i> and a shift towards M2-like polarization when compared to <i>Mir34a</i>-proficient BMDMs. Concomitant deletion of <i>Csf1r</i> or treatment with a <i>Csf1r</i> inhibitor reduced the CAC burden and invasion in these mice. Notably, loss of myeloid Mir34a function resulted in a prominent, inflammatory CAC cell subtype, which displayed epithelial and macrophage markers. These cells displayed high levels of the EMT transcription factor Zeb2 and may therefore enhance the invasiveness of CACs. Taken together, our results provide in vivo evidence for a tumor suppressive role of myeloid <i>Mir34a</i> in CACs which is, at least in part, mediated by maintaining macrophages in an M1-like state via repression of Mir34a targets, such as <i>Csf1r</i>. Collectively, these findings may serve to identify new therapeutic targets and approaches for treatment of CAC.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"232 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring fructose metabolism as a potential therapeutic approach for pancreatic cancer","authors":"Chengqiang Wang,&nbsp;Lu Wang,&nbsp;Qing Zhao,&nbsp;Jiao Ma,&nbsp;Yitao Li,&nbsp;Junliang Kuang,&nbsp;Xintong Yang,&nbsp;Huichang Bi,&nbsp;Aiping Lu,&nbsp;Kenneth C. P. Cheung,&nbsp;Gerry Melino,&nbsp;Wei Jia","doi":"10.1038/s41418-024-01394-3","DOIUrl":"10.1038/s41418-024-01394-3","url":null,"abstract":"Excessive fructose intake has been associated with the development and progression of pancreatic cancer. This study aimed to elucidate the relationship between fructose utilization and pancreatic cancer progression. Our findings revealed that pancreatic cancer cells have a high capacity to utilize fructose and are capable of converting glucose to fructose via the AKR1B1-mediated polyol pathway, in addition to uptake via the fructose transporter GLUT5. Fructose metabolism exacerbates pancreatic cancer proliferation by enhancing glycolysis and accelerating the production of key metabolites that regulate angiogenesis. However, pharmacological blockade of fructose metabolism has been shown to slow pancreatic cancer progression and synergistically enhance anti-tumor capabilities when combined with anti-angiogenic agents. Overall, targeting fructose metabolism may prove to be a promising therapeutic approach in the treatment of pancreatic cancer.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 12","pages":"1625-1635"},"PeriodicalIF":13.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AKR1B1-dependent fructose metabolism enhances malignancy of cancer cells","authors":"Qing Zhao,&nbsp;Bing Han,&nbsp;Lu Wang,&nbsp;Jia Wu,&nbsp;Siliang Wang,&nbsp;Zhenxing Ren,&nbsp;Shouli Wang,&nbsp;Haining Yang,&nbsp;Michele Carbone,&nbsp;Changsheng Dong,&nbsp;Gerry Melino,&nbsp;Wen-Lian Chen,&nbsp;Wei Jia","doi":"10.1038/s41418-024-01393-4","DOIUrl":"10.1038/s41418-024-01393-4","url":null,"abstract":"Fructose metabolism has emerged as a significant contributor to cancer cell proliferation, yet the underlying mechanisms and sources of fructose for cancer cells remain incompletely understood. In this study, we demonstrate that cancer cells can convert glucose into fructose through a process called the AKR1B1-mediated polyol pathway. Inhibiting the endogenous production of fructose through AKR1B1 deletion dramatically suppressed glycolysis, resulting in reduced cancer cell migration, inhibited growth, and the induction of apoptosis and cell cycle arrest. Conversely, the acceleration of endogenous fructose through AKR1B1 overexpression has been shown to significantly enhance cancer cell proliferation and migration with increased S cell cycle progression. Our findings highlight the crucial role of endogenous fructose in cancer cell malignancy and support the need for further investigation into AKR1B1 as a potential cancer therapeutic target.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 12","pages":"1611-1624"},"PeriodicalIF":13.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41418-024-01393-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SOX4 facilitates brown fat development and maintenance through EBF2-mediated thermogenic gene program in mice","authors":"Shuai Wang, Ting He, Ya Luo, Kexin Ren, Huanming Shen, Lingfeng Hou, Yixin Wei, Tong Fu, Wenlong Xie, Peng Wang, Jie Hu, Yu Zhu, Zhengrong Huang, Qiyuan Li, Weihua Li, Huiling Guo, Boan Li","doi":"10.1038/s41418-024-01397-0","DOIUrl":"https://doi.org/10.1038/s41418-024-01397-0","url":null,"abstract":"<p>Brown adipose tissue (BAT) is critical for non-shivering thermogenesis making it a promising therapeutic strategy to combat obesity and metabolic disease. However, the regulatory mechanisms underlying brown fat formation remain incompletely understood. Here, we found SOX4 is required for BAT development and thermogenic program. Depletion of SOX4 in BAT progenitors (<i>Sox4-MKO</i>) or brown adipocytes (<i>Sox4-BKO</i>) resulted in whitened BAT and hypothermia upon acute cold exposure. The reduced thermogenic capacity of <i>Sox4-MKO</i> mice increases their susceptibility to diet-induced obesity. Conversely, overexpression of SOX4 in BAT enhances thermogenesis counteracting diet-induced obesity. Mechanistically, SOX4 activates the transcription of EBF2, which determines brown fat fate. Moreover, phosphorylation of SOX4 at S235 by PKA facilitates its nuclear translocation and EBF2 transcription. Further, SOX4 cooperates with EBF2 to activate transcriptional programs governing thermogenic gene expression. These results demonstrate that SOX4 serves as an upstream regulator of EBF2, providing valuable insights into BAT development and thermogenic function maintenance.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"11 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of BAK-mediated apoptosis by the BH3-only protein BNIP5","authors":"Sebastian Rühl, Zhenrui Li, Shagun Srivastava, Luigi Mari, Clifford S. Guy, Mao Yang, Tudor Moldoveanu, Douglas R. Green","doi":"10.1038/s41418-024-01386-3","DOIUrl":"https://doi.org/10.1038/s41418-024-01386-3","url":null,"abstract":"<p>BCL-2 family proteins regulate apoptosis by initiating mitochondrial outer membrane permeabilization (MOMP). Activation of the MOMP effectors BAX and BAK is controlled by the interplay of anti-apoptotic BCL-2 proteins (e.g., MCL-1) and pro-apoptotic BH3-only proteins (e.g., BIM). Using a genome-wide CRISPR-dCas9 transactivation screen we identified BNIP5 as an inhibitor of BAK-, but not BAX-induced apoptosis. BNIP5 blocked BAK activation in different cell types and in response to various cytotoxic therapies. The BH3 domain of BNIP5 was both necessary and sufficient to block BAK activation. Mechanistically, the BH3 domain of BNIP5 acts as a selective BAK activator, but a poor de-repressor of complexes between BAK and pro-survival BCL-2 family proteins. By promoting the binding of activated BAK to MCL-1 or BCL-xL, BNIP5 inhibits apoptosis when BAX is absent. Based on our observations, BNIP5 can act functionally as an anti-apoptotic BH3-only protein.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"6 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}