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Gambogic acid (GA) inhibits the proliferation of various human cancer cells. However, because of its water insolubility, the antitumor efficacy of GA is limited. Objectives. To investigate the antitumor activity of gambogic acid lysinate (GAL) and its mechanism. Methods. Inhibition of cell proliferation was determined by MTT assay; intracellular ROS level was detected by staining cells with DCFH-DA; cell apoptosis was determined by flow cytometer and the mechanism of GAL was investigated by Western blot. Results. GAL inhibited the proliferation of MCF-7 cells with IC50 values 1.46 µmol/L comparable with GA (IC50, 1.16 µ mol/L). GAL promoted the production of ROS; however NAC could remove ROS and block the effect of GAL. GAL inhibited the expression of SIRT1 but increased the phosphorylation of FOXO3a and the expression of p27Kip1. At knockdown of FOXO3a, cell apoptosis induced by GAL can be partly blocked. In addition it also enhanced the cleavage of caspase-3. Conclusions. GAL inhibited MCF-7 cell proliferation and induced MCF-7 cell apoptosis by increasing ROS level which could induce cell apoptosis by both SIRT1/FOXO3a/p27Kip1 and caspase-3 signal pathway. These results suggested that GAL might be useful as a modulation agent in cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract: HER2-positive cancers represent a class of malignancies with high metastasis and poor prognosis. We previously generated the e23sFv-PEA II-casp6 recombinant, which contains an anti-HER2 single-chain antibody (e23sFv), a Pseudomonas exotoxin A translocation domain (PEA II), and a constitutively active caspase-6 (casp6), and demonstrated its potent selective anti-tumor activities. In this study, we generated a smaller-sized recombinant e23sFv-Fdt-casp6, in which the PEA II domain was replaced with the furin cleavage sequence from diphtheria toxin (Fdt), and explored its translocation pathway and specific killing mechanism. We found that e23sFv-Fdt-casp6 proteins, following their receptor-mediated endocytosis in HER2-positive gastric cancer cells, underwent furin-mediated cleavage in endosome and engaged in direct translocation of the released C-terminal fragment (active caspase-6) instead of via the trans-Golgi and the endoplasmic reticulum (ER) pathway. The active caspase-6 cleaved its well-documented substrate, Lamin A, and subsequently triggered the apoptosis of cancer cells. The e23sFv-Fdt-casp6 proteins produced from genetically modified cells showed a selective cytotoxicity to cultured HER2-positive gastric cancer cells. Similar to the results of our previous research on e23sFv-PEA II-casp6, the delivery of liposome-encapsulated e23sFv-Fdt-casp6 constructs in tumor-adjacent muscles also inhibited tumor growth and prolonged animal survival in a nude mouse xenograft tumor model. Moreover, e23sFv-Fdt-casp6 proteins were also cytotoxic to trastuzumab-resistant gastric cancer cells characterized by downregulated HER2 expression. Accordingly, e23sFv-Fdt-casp6 recombinant provides a promising therapeutic alternative for HER2-positive and trastuzumab-resistant gastric cancers. [Copyright &y& Elsevier]

Pyroptosis is a type of programmed cell death and plays a dual role in distinct cancers. It is elusive to evaluate the activation level of pyroptosis and to appraise the involvement of pyroptosis in the occurrence and development of diverse tumors. Accordingly, we herein established an indicator to evaluate pyroptosis related gene transcription levels based on the expression level of genes involved in pyroptosis and tried to elaborated on the association between pyroptosis and tumors across diverse tumor types. We found that pyroptosis related gene transcription levels could predict the prognosis of patients, which could act as either a favorable or a dreadful factor in diverse cancers. According to signaling pathway analyses we observed that pyroptosis played a significant role in immune regulation and tumorigenesis and had strong links with other forms of cell death. We also performed analysis on the crosstalk between pyroptosis and immune status and further investigated the predictive potential of pyroptosis level for the efficacy of immunotherapy. Lastly, we manifested that pyroptosis status could serve as a biomarker to the efficacy of chemotherapy across various cancers. In summary, this study established a quantitative indicator to evaluate pyroptosis related gene transcription levels, systematically explored the role of pyroptosis in pan-cancer. These results could provide potential research directions targeting pyroptosis, and highlighted that pyroptosis may be used to develop a novel strategy for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Pyroptosis is a type of programmed cell death and plays a dual role in distinct cancers. It is elusive to evaluate the activation level of pyroptosis and to appraise the involvement of pyroptosis in the occurrence and development of diverse tumors. Accordingly, we herein established an indicator to evaluate pyroptosis related gene transcription levels based on the expression level of genes involved in pyroptosis and tried to elaborated on the association between pyroptosis and tumors across diverse tumor types. We found that pyroptosis related gene transcription levels could predict the prognosis of patients, which could act as either a favorable or a dreadful factor in diverse cancers. According to signaling pathway analyses we observed that pyroptosis played a significant role in immune regulation and tumorigenesis and had strong links with other forms of cell death. We also performed analysis on the crosstalk between pyroptosis and immune status and further investigated the predictive potential of pyroptosis level for the efficacy of immunotherapy. Lastly, we manifested that pyroptosis status could serve as a biomarker to the efficacy of chemotherapy across various cancers. In summary, this study established a quantitative indicator to evaluate pyroptosis related gene transcription levels, systematically explored the role of pyroptosis in pan-cancer. These results could provide potential research directions targeting pyroptosis, and highlighted that pyroptosis may be used to develop a novel strategy for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Wild-type p53-induced phosphatase (Wip1) is a member of the protein phosphatase type 2C family and is an established oncogene due to its dephosphorylation of several tumor suppressors and negative control of the DNA damage response system. It has been reported to dephosphorylate p53, ataxia telangiectasia mutated, checkpoint kinase 1 and p38 mitogen activated protein kinases, forming negative feedback loops to inhibit apoptosis and cell cycle arrest. Wip1 serves a major role in tumorigenesis, progression, invasion, distant metastasis and apoptosis in various types of human cancer. Therefore, it may be a potential biomarker and therapeutic target in the diagnosis and treatment of cancer. Furthermore, previous evidence has revealed a new role for Wip1 in the regulation of chemotherapy resistance. In the present review, the current knowledge on the role of Wip1 in cancer is discussed, as well as its potential as a novel target for cancer treatment and its function in chemotherapy resistance. [ABSTRACT FROM AUTHOR]

To explore the mechanism underlying antileukaemia effect of sodium valproate, the growth and survival of the K562 cell line were investigated. Global profiles of gene expression in K562 cells exposed to sodium valproate were assessed and validated. The differentially expressed genes identified were further used to query the connectivity map database to retrieve a ranked list of compounds that act on the same intracellular targets as sodium valproate. A significant increase in cell apoptosis and a change in gene expression profile were observed in valproate-exposed K562 cells. The significant enrichment analysis of gene ontology terms for the differentially expressed genes showed that these genes were involved in many important biological processes. Eight differentially expressed genes involved in apoptosis were verified by quantitative real-time PCR. The connectivity map analysis showed gene expression profile in K562 cells exposed to sodium valproate was most similar to that of HDACi and PI3K inhibitors, suggesting that sodium valproate might exert antileukaemic action by inhibiting HDAC as well as inhibiting PI3K pathway. In conclusion, our data might provide clues to elucidate the molecular and therapeutic potential of VPA in leukaemia treatment, and the connectivity map is a useful tool for exploring the molecular mechanism of drug action. [ABSTRACT FROM AUTHOR]

Backgound: The mechanistic target of rapamycin complex 1 (mTORC1) is important in the development and progression of many cancers. Targeted cancer therapy using mTORC1 inhibitors is used for treatment of cancers; however, their clinical efficacies are still limited.Methods: We recently created a new mouse model for human lymphangiosarcoma by deleting Tsc1 in endothelial cells and consequent hyper-activation of mTORC1. Using Tsc1iΔEC tumour cells from this mouse model, we assessed the efficacies of histone deacetylase (HDAC) inhibitors as anti-tumour agents for mTORC1-driven tumours.Results: Unlike the cytostatic effect of mTORC1 inhibitors, HDAC inhibitors induced Tsc1iΔEC tumour cell death in vitro and their growth in vivo. Analysis of several HDAC inhibitors suggested stronger anti-tumour activity of class I HDAC inhibitor than class IIa or class IIb inhibitors, but these or pan HDAC inhibitor SAHA did not affect mTORC1 activation in these cells. Moreover, HDAC inhibitor-induced cell death required elevated autophagy, but was not affected by disrupting caspase-dependent apoptosis pathways. We also observed increased reactive oxygen species and endoplasmic reticulum stress in SAHA-treated tumour cells, suggesting their contribution to autophagic cell death, which were dependent on mTORC1 hyper-activation.Conclusion: These studies suggest a potential new treatment strategy for mTORC1-driven cancers like lymphangiosarcoma through an alternative mechanism. [ABSTRACT FROM AUTHOR]

Loss of sirtuin 1 (SIRT1) activity may be associated with metabolic diseases, including diabetes. The aim of the present study was to investigate the potential effects of overexpressed endothelial nitric oxide synthase (eNOS) on cell proliferation and apoptosis with SIRT1 activation in the Min6 mouse pancreatic ß cell line. A pcDNA3.0-eNOS plasmid was constructed and transfected into Min6 cells for 24 h prior to harvesting. eNOS expression was validated and SIRT1 expression was detected following plasmid transfection using reverse transcription-quantitative polymerase chain reaction and western blot analysis, which demonstrated that the expression levels of eNOS and SIRT1 were significantly upregulated. Furthermore, the cell proliferation and cell apoptosis of the Min6 cells were evaluated, using a cell counting kit-8 assay and flow cytometry, respectively. The results suggested that overexpressed eNOS promoted cell proliferation and inhibited cell apoptosis in Min6 cells. The interaction between eNOS and SIRT1 was explored through co-immunoprecipitation, and it found that there was a strong interaction between eNOS and SIRT1. In conclusion, overexpressed eNOS may induce SIRT1 activation, which is implied to play a protective role in Min6 cells, and eNOS may be a new therapeutic target for diseases such as type 2 diabetes. [ABSTRACT FROM AUTHOR]

Purpose: To formulate trimethyl chitosan-functionalized retinoic acid-encapsulated solid lipid nanoparticles for the effective treatment of glioma. Methods: Retinoic acid-loaded solid lipid nanoparticles (R-SLNs) were prepared using homogenization followed by sonication. R-SLN surfaces were functionalized electrostatically with trimethyl chitosan as a nanocarrier (TR-SLNs) with enhanced anti-cancer activity. They were evaluated by dynamic light scattering (DLS), scanning electron microscopy, in vitro drug release, and cell cytotoxicity and apoptosis studies. Results: Morphological images showed spherical and uniformly dispersed nanoparticles. A sustained monophasic release pattern was observed throughout the study period. Furthermore, the anti-cancer effect of TR-SLNs was demonstrated by increased cell killing activity compared with the free drug (p < 0.01); negligible cytotoxicity was observed with blank carriers. Apoptosis assay showed increased cell populations in early/late apoptotic and necrotic phases. Conclusion: This study showed the potential application of surface-modified solid lipid nanoparticles for the effective treatment of brain cancer. [ABSTRACT FROM AUTHOR]

Background: Chronic myelogenous leukemia (CML) is a hematological stem cell disorder. Tyrosine kinase inhibitors (TKIs) are the standard treatments for CML, but a number of patients fail to respond effectively due to gene mutations. Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, has been shown to have anti-tumor effect on solid tumor whereas the anti-CML effect and its underlying mechanism have not been completely elucidated.Methods: The cytotoxic effects of celecoxib and/or imatinib were evaluated by MTT assay. Cell cycle distribution was examined by propidium iodide (PI) assay. Apoptosis or necrosis was analyzed by Annexin-V/PI, Hoechst 33342 staining and Western blot assays. Autophagy suppression effect of celecoxib was examined by Western blot and LysoTracker probe labelling. Lysosensor probe labelling was used to detect the effect of celecoxib on the lysosomal function.Results: In this study, we found that celecoxib had therapy efficacy in KBM5 and imatinib-resistant KBM5-T315I CML cell lines. Celecoxib caused significant cytotoxic effect in both cell lines, especially in KBM5-T315I cells exposed to celecoxib for 72 h. Moreover, celecoxib induced necrosis and apoptosis while inhibited autophagy in CML cell lines and patient samples. Furthermore, this study demonstrated that celecoxib prevented the autophagic flux by inhibiting lysosome function. Celecoxib was tested in combination with imatinib, demonstrating that celecoxib could strengthen the cytotoxicity of imatinib in imatinib-resistant CML cells.Conclusions: These findings showed that celecoxib had therapy efficacy on CML cells. And it is first time to demonstrate that celecoxib is an autophagy suppresser and a combination of celecoxib and imatinib might be a promising new therapeutic strategy for imatinib-resistant CML cells. [ABSTRACT FROM AUTHOR]

Previous studies have reported that mTORC2 promotes cell survival through phosphorylating AKT and enhancing its activity. We reveal another mechanism by which mTORC2 controls apoptosis. Inactivation of mTORC2 promotes binding of CIP2A to PP2A, leading to reduced PP2A activity toward c-Myc serine 62 and, consequently, enhancement of c-Myc phosphorylation and expression. Increased c-Myc activity induces transcription of pri-miR-9-2/miR-9-3p, in turn inhibiting expression of E2F1, a transcriptional factor critical for cancer cell survival and tumor progression, resulting in enhanced apoptosis. In vivo experiments using B cell-specific mTORC2 (rapamycin-insensitive companion of mTOR) deletion mice and a xenograft tumor model confirmed that inactivation of mTORC2 causes up-regulation of c-Myc and miR-9-3p, down-regulation of E2F1, and consequent reduction in cell survival. Conversely, Antagomir-9-3p reversed mTORC1 /2 inhibitor-potentiated E2F1 suppression and resultant apoptosis in xenograft tumors. Our in vitro and in vivo findings collectively demonstrate that mTORC2 promotes cell survival by stimulating E2F1 expression through a c-Myc-and miR-9-3p-dependent mechanism. [ABSTRACT FROM AUTHOR]

The expression of focal adhesion kinase family interacting protein of 200-kDa (FIP200) in normal brain is limited to some neurons and glial cells. On immunohistochemical analysis of biopsies of glioblastoma tumors, we detected FIP200 in the tumor cells, tumor-associated endothelial cells, and occasional glial cells. Human glioblastoma tumor cell lines and immortalized human astrocytes cultured in complete media also expressed FIP200 as did primary human brain microvessel endothelial cells (MvEC), which proliferate in culture and resemble reactive endothelial cells. Downregulation of endogenous expression of FIP200 using small interfering RNA resulted in induction of apoptosis in the human glioblastoma tumor cells, immortalized human astrocytes, and primary human brain MvEC. It has been shown by other investigators using cells from other tissues that FIP200 can interact directly with, and inhibit, proline-rich tyrosine kinase 2 (Pyk2) and focal adhesion kinase (FAK). In the human glioblastoma tumor cells, immortalized human astrocytes, and primary human brain MvEC, we found that downregulation of FIP200 increased the activity of Pyk2 without increasing its expression, but did not affect the activity or expression of FAK. Coimmunoprecipitation and colocalization studies indicated that the endogenous FIP200 was largely associated with Pyk2, rather than FAK, in the glioblastoma tumor cells and brain MvEC. Moreover, the pro-apoptotic effect of FIP200 downregulation was inhibited significantly by a TAT-Pyk2-fusion protein containing the Pyk2 autophosphorylation site in these cells. In summary, downregulation of endogenous FIP200 protein in glioblastoma tumor cells, astrocytes, and brain MvECs promotes apoptosis, most likely due to the removal of a direct interaction of FIP200 with Pyk2 that inhibits Pyk2 activation, suggesting that FIP200 expression may be required for the survival of all three cell types found in glioblastoma tumors. [ABSTRACT FROM AUTHOR]

Background: Aurora kinase ensures accurate chromosome segregation during cell cycle, maintaining genetic integrity in cell division. VX-680, a small-molecule Aurora kinase inhibitor, interferes with mitotic entry and formation of bipolar spindles. Here, we evaluated VX-680 as a potential agent for treatment of all-trans retinoid acid (ATRA)-resistant acute promyelocytic leukemia (APL) in vitro.Methods: CD11b expression was utilized to assess cell differentiation by flow cytometry. Immunofluorescence staining was conducted to analyze formation of cell monopolar spindle. Cell proliferation was evaluated by MTT assay. Sub-G1 population and Annexin V/PI staining were used to measure cell apoptosis. Hoechst 33342 staining was applied for identifying morphological changes in nucleus of apoptotic cell. Aurora-A (Aur-A) activation and the signaling pathways involved in apoptosis were detected by Western blot. JC-1 probe was employed to measure mitochondrial depolarization.Results: VX-680 inhibited Aur-A by reducing autophosphorylation at the activation site, Thr288, accompanied by producing monopolar mitotic spindles in APL cell line NB4-R2 that was resistant to ATRA. In addition, we found that VX-680 inhibited cell proliferation as assessed by MTT assay. Flow cytometry showed that VX-680 led to apoptotic cell death in both dose- and time-dependent manners by either Sub-G1 or Annexin V/PI analysis. Hoechst 33342 staining represented typical apoptotic cells with nuclear fragmentation in VX-680 treated cells. Importantly, VX-680 inhibition of Aurora kinase suppressed Akt-1 activation and induced mitochondrial depolarization, which eventually resulted in apoptosis by activation of caspase pathway, as indicated by increasing proteolytic cleavage of procaspase-3 and poly ADP ribose polymerase (PARP) in NB4-R2 cells.Conclusions: Our study suggested potential clinical use of mitotic Aurora kinase inhibitor in targeting ATRA-resistant leukemic cells. [ABSTRACT FROM AUTHOR]

Focal adhesion kinase (FAK) is essential for vascular development as endothelial cell (EC)-specific knockout of FAK (conditional FAK knockout [CFKO] mice) leads to embryonic lethality. In this study, we report the differential kinase-independent and -dependent functions of FAK in vascular development by creating and analyzing an EC-specific FAK kinase-defective (KD) mutant knockin (conditional FAK knockin [CFKI]) mouse model. CFKI embryos showed apparently normal development through embryonic day (E) 13.5, whereas the majority of CFKO embryos died at the same stage. Expression of KD FAK reversed increased EC apoptosis observed with FAK deletion in embryos and in vitro through suppression of up-regulated p21. However, vessel dilation and defective angiogenesis of CFKO embryos were not rescued in CFKI embryos. ECs without FAK or expressing KD FAK showed increased permeability, abnormal distribution of vascular endothelial cadherin (VE-cadherin), and reduced VE-cadherin Y658 phosphorylation. Together, our data suggest that kinase-independent functions of FAK can support EC survival in vascular development through E13.5 but are insufficient for maintaining EC function to allow for completion of embryogenesis. [ABSTRACT FROM AUTHOR]

Tanshinone I (Tan-I) is a diterpene quinone extracted from the traditional herbal medicine Salvia miltiorrhiza Bunge. Recently, Tan-I has been reported to have anti-tumor effects. In this study, we investigated the growth inhibition and apoptosis inducing effects of Tan-I on three kinds of monocytic leukemia cells (U937, THP-1 and SHI 1). Cell viability was measured by MTT assay. Cell apoptosis was assessed by flow cytometry (FCM) and AnnexinV/PI staining. Reverse transcriptase polymerase chain reaction (RT-PCR) and PCR-enzyme-linked immunosorbent assay (ELISA) were used to detect human telomerase reverse transcriptase (hTERT) expression and telomerase activity before and after apoptosis. The activity of caspase-3 was determined by Caspase colorimetric assay kit and Western blot analysis. Expression of the anti-apoptotic gene Survivin was assayed by Western blot and Real-time RT-PCR using the ABI PRISM 7500 Sequence Detection System. The results revealed that Tan-I could inhibit the growth of these three kinds of leukemia cells and cause apoptosis in a time- and dose-dependent manner. After treatment by Tan-I for 48 h, Western blotting showed cleavage of the caspase-3 zymogen protein with the appearance of its 17-kD subunit, and a 89-kD cleavage product of poly (ADP-ribose) polymerase (PARP), a known substrate of caspase-3, was also found clearly. The expression of hTERT mRNA as well as activity of telomerase were decreased concurrently in a dose-dependent manner. Moreover, Real-time RT-PCR and Western blot revealed a significant down-regulation of Survivin. We therefore conclude that the induction of apoptosis by Tan-I in monocytic leukemia U937 THP-1 and SHI 1 cells is highly correlated with activation of caspase-3 and decreasing of hTERT mRNA expression and telomerase activity as well as down-regulation of Survivin expression. To our knowledge, this is the first report about the effects of Tan-I on monocytic leukemia cells. [ABSTRACT FROM AUTHOR]

FIP200 (FAK family-interacting protein of 200 kDa) is a conserved protein recently identified as a potential mammalian counterpart of yeast autophagy protein Atgl7. However, it remains unknown whether mammalian FIP200 regulates autophagy in vivo. Here we show that neural-specific deletion of FIP200 resulted in cerebellar degeneration accompanied by progressive neuronal loss, spongiosis, and neurite degeneration in the cerebellum. Furthermore, deletion of FIP200 led to increased apoptosis in cerebellum as well as accumulation of ubiquitinated protein aggregates without any deficiency in proteasome catalytic functions. We also observed an increased p62/SQSTM1 accumulation in the cerebellum and reduced autophagosome formation as well as accumulation of damaged mitochondria in the mutant mice. Lastly, analysis of cerebellar neurons in vitro showed reduced JNK activation and increased susceptibility to serum deprivation-induced apoptosis in cerebellar neurons from the mutant mice. Taken together, these results provide strong genetic evidence for a role of FIP200 in the regulation of neuronal homeostasis through its function in autophagy in vivo. [ABSTRACT FROM AUTHOR]

Mast cells play an important role in both allergy and innate immunity. Recently, we demonstrated an active interaction between human mast cells and Pseudomonas aeruginosa leading to the production of multiple cytokines. Here, we show that both primary cultured human cord blood-derived mast cells and the human mast cell line I-IMC.1 undergo apoptosis as determined by single-stranded DNA (ssDNA) formation after stimulation with P. aeruginosa exotoxin A (ETA), a major toxin produced by this bacterium. ETA-induced ssDNA formation was completely inhibited by Z-VAD (where Z is benzyloxycarbonyl), which blocks multiple caspases, suggesting a role for caspases in this process. Active caspase-3 formation in mast cells after an ETA challenge was detected by both Western blotting and flow cytometry analysis. ETA-induced caspase-3 activity in human mast cells was demonstrated by the detection of a characteristic 23 kDa product of D4-GDI (where GDI is guanine nucleotide dissociation inhibitor), an endogenous caspase-3 substrate. Interestingly, a specific caspase-8 inhibitor, Z-IETD-fmk (where fmk is fluoromethyl ketone), blocked ETA-induced cleavage of D4-GDI, but a caspase-9 inhibitor (Z-LEHD-fmk) did not. Treatment of mast cells with caspase-3 inhibitor Z-DEVD-fmk or caspase-8 inhibitor Z-IETD-fmk reduced the generation of ssDNA induced by ETA, suggesting a role for caspase-8 and -3 in ETA-induced mast cell apoptosis. Furthermore, treatment of mast cells with ETA induced decreases of the short form and a long form (p43) of Fas-associated death domain protein (FADD)-like interleukin-1β-converting enzyme (FLICE) (caspase-8)-inhibitory proteins (FLIPs), which are endogenous caspase-8 inhibitors. Taken together, these results suggest that ETA-induced mast cell apoptosis involves down-regulation of antiapoptotic proteins, FLIPs, and activation of caspase-8 and -3 pathways. [ABSTRACT FROM AUTHOR]

Autophagy is an evolutionarily conserved cellular process controlled through a set of essential autophagy genes (Atgs). However, there is increasing evidence that most, if not all, Atgs also possess functions independent of their requirement in canonical autophagy, making it difficult to distinguish the contributions of autophagy-dependent or -independent functions of a particular Atg to various biological processes. To distinguish these functions for FIP200 (FAK family-interacting protein of 200 kDa), an Atg in autophagy induction, we examined FIP200 interaction with its autophagy partner, Atg13. We found that residues 582-585 (LQFL) in FIP200 are required for interaction with Atg13, and mutation of these residues to AAAA (designated the FIP200-4A mutant) abolished its canonical autophagy function in vitro. Furthermore, we created a FIP200-4A mutant knock-in mouse model and found that specifically blocking FIP200 interaction with Atg13 abolishes autophagy in vivo, providing direct support for the essential role of the ULK1/Atg13/FIP200/Atg101 complex in the process beyond previous studies relying on the complete knockout of individual components. Analysis of the new mouse model showed that nonautophagic functions of FIP200 are sufficient to fully support embryogenesis by maintaining a protective role in TNFα-induced apoptosis. However, FIP200-mediated canonical autophagy is required to support neonatal survival and tumor cell growth. These studies provide the first genetic evidence linking an Atg's autophagy and nonautophagic functions to different biological processes in vivo. [ABSTRACT FROM AUTHOR]