Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome
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ABSTRACT:
PROVIDER: PRJNA551425 | ENA |
REPOSITORIES: ENA
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Project description:miR-30d has been identified in this study as a novel onco-miRNA downstream of mutant p53. Here we report the microarray data obtained in MDA-MB-231 in which miR-30d levels and function were stably inhibited by a decoy construct (dy_30d)
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Project description:TP53 missense mutations leading to the expression of mutant p53 oncoproteins are frequent driver events during tumorigenesis. p53 mutants promote tumor growth, metastasis and chemoresistance by affecting fundamental cellular pathways and functions. Here, we demonstrate that p53 mutants modify structure and function of the Golgi apparatus, culminating in the increased release of a pro-malignant secretome by tumor cells and primary fibroblasts from patients with Li-Fraumeni cancer predisposition syndrome. Mechanistically, interacting with the hypoxia responsive factor HIF1α, mutant p53 induces the expression of miR-30d, which in turn causes tubulo-vesiculation of the Golgi apparatus, leading to enhanced vesicular trafficking and secretion. The mut-p53/HIF1α/miR-30d axis potentiates the release of soluble factors and the deposition and remodeling of the ECM, affecting mechano-signaling and stromal cells activation within the tumor microenvironment, thereby enhancing tumor growth and metastatic colonization.
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Project description:The process of aging is associated with disturbed mineral homeostasis, such as zinc deficiency. Simultaneously, cellular response to external stimuli, including receptor signaling and DNA repair response diminishes, and epigenetic dysregulation occurs. The Golgi apparatus plays various roles in the cell; however, the effect of aging on the morphology and function of the Golgi apparatus and the impact of Golgi senescence in cellular activity remains unknown. In the present study, we found that Golgi stress is associated with senescent cell irresponsiveness to external stimuli. The senescent Golgi was associated with a disassembled microtubule network in the Golgi and perinuclear areas. These effects could be reproduced by disruption of the Golgi-associated microtubules or zinc depletion. To clarify the importance of Golgi-zinc homeostasis in more detail, the implications of the Golgi-zinc transporter ZIP13 were analyzed; Zip13-deficient mice Golgi exhibited morphology similar to that of senescent Golgi. Additionally, fibroblasts from Zip13-deficient mice showed dysregulation of DNA repair and cellular acetylation with downregulated nuclear translocation of p300, HDAC1/2, and p53 proteins, which are reminiscent characteristics of senescent cells. Our findings demonstrate the underlying reason for senescent cell irresponsiveness to various stimuli and highlight the importance of a zinc-rich diet during aging.
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Project description:Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post59 translational cancer hallmark and the consequences thereof remain elusive. Here we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In both cancer cell cultures and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycomes revealed that fucosylation of the antioxidant PON1 is a critical component of the therapy66 induced secretome. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Non-specific and PON1-specific secretome deglycosylation both limited the expansion of resistant clones in a tumor regression model. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance.
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Project description:Secretome is intimately linked to Golgi apparatus (GA) which acts as a transition platform of proteins processing and sorting in trafficking pathways. GA-associated secretome runs through the endomembrane system and is critical for inter- and intracellular communication networks. However, achieving in situ dissection of GA-associated secretome remains challenging owing to the lack of efficient labeling methods. Herein, we described an aggregation-induced emission luminogen-mediated photocatalytic proximity labeling strategy (AIE-PhoPL) that allowed dynamic profiling of GA-associated secretome with high spatiotemporal precision in minutes. With the GA-targeting photocatalyst based on aggregation-induced emission luminogen (AIEgen), the proteins were labeled locally in Golgi lumen with high efficiency under light, enabling spatiotemporally resolved modifying of histidine and tyrosine residues. AIE-PhoPL strategy was successfully utilized in living HeLa and hard-to-transfect macrophage HMC3 cells by determining a significant subset of GA-associated secretome with 80% specificity, linking the distinct GA-associated secretory profiles to cellular characteristics. We further applied AIE-PhoPL to dynamic proteome mapping of brain and bone metastatic lung cancer cells, which revealed GA-associated secretory proteomic patterns related to metastatic mechanisms and the underlying roles GA-associated secretion played in extracellular matrix organization during metastasis. This work provides a powerful tool to break out the dilemma for chemical labeling of GA-associated secretome in living cells and fuels the research on diversification of controllable chemical probes for subcellular proteome labeling.
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Project description:p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR)
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Project description:We explore the transcriptional response of mammalian cells undergoing various insults to Golgi homeostasis. HEK293 cells (Flp-In T-REx 293 cells) stably containing a doxycycline-inducible Golgi-localized HaloTag2 construct (GA-HT2) were treated with the ionophore nigericin, the glycosylation inhibitor xyloside, or were induced by doxycycline and treated with the hydrophobic tag HyT36 to induce destabilization of GA-HT2. We found that while nigericin and xyloside induce global transcriptional changes, destabilization of GA-HT2 induces a Golgi-specific response.
2018-06-21 | GSE99490 | GEO
Project description:TGFβ ligands act as tumor suppressors in early stage tumors but are paradoxically diverted into potent prometastatic factors in advanced cancers. The molecular nature of this switch remains enigmatic. We now show that TGFβ-dependent cell migration, invasion and metastasis are empowered by mutant-p53. To investigate the specific gene expression program by which mutant-p53 and TGFβ control invasion and metastasis in breast cancer cells, we compared the TGFβ transcriptomic profile of control and mutant-p53 depleted MDA-MB-231 cells. Experiment Overall Design: MDA-MB-231 cells, stably expressing either control (shGFP) or anti-p53 (shp53) short-hairpin RNAs, were left untreated or treated with TGFbeta. Samples were then processed for total RNA extraction and hybridization on Affymetrix microarrays. Four biological replicas (A, B, C, D) were used for each of the 4 conditions (1: untreated control; 2: TGFbeta treated control; 3: untreated p53-depleted cells; 4: TGFbeta treated mutant-p53-depleted cells), for a total of 16 samples.
2009-04-11 | E-GEOD-14491 | biostudies-arrayexpress