PiRNA-independent Function of PIWIL1 as a Novel co-activator for Anaphase Promoting Complex/Cyclosome (APC/C) to Drive Pancreatic Cancer Metastasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA593186 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10581600.fastq.gz | Fastqsanger.gz | |||
| SRR10581601.fastq.gz | Fastqsanger.gz | |||
| SRR10581602.fastq.gz | Fastqsanger.gz | |||
| SRR10581597.fastq.gz | Fastqsanger.gz | |||
| SRR10581598.fastq.gz | Fastqsanger.gz |
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Project description:Piwi proteins are normally restricted in germ cells to suppress transposons through association with piRNAs, but are also frequently activated in many types of human cancers. Of great puzzle is the lack of induction of corresponding piRNAs in cancer cells, as we document here in human pancreatic ductal adenocarcinomas (PDAC), implying that such germline-specific proteins are somehow hijacked to promote tumorigenesis through different mode of action. To pursue the underlying mechanism, we now demonstrate that in the absence of piRNAs, the aberrantly induced human PIWIL1 in PDAC functions as an oncoprotein by activating the Anaphase Promoting Complex/Cyclosome (APC/C), which then targets a critical cell adhesion-related protein Pinin to enhance PDAC metastasis. This is in contrast to piRNA-dependent PIWIL1 ubiquitination and removal by APC/C during late spermiogenesis. These findings thus unveil an piRNA-dependent mechanism to switch PIWIL1 from a substrate in spermatids to a co-activator of APC/C in human cancer cells.
2020-02-01 | GSE141340 | GEO
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2020-08-05 | E-MTAB-8121 | biostudies-arrayexpress
Project description:In order to investigate the dynamic regulation of the APC/C by intrinsically disordered regions (IDRs) upon phosphorylation, we employed cross-linking mass spectrometry (CLMS). Given that the phosphorylation of Apc1-300L (IDR in Apc1) is a key determinant in its release from the co-activator binding site, we compared the interaction profiles of unphosphorylated and hyper-phosphorylated rAPC/C_WT complexes. The CLMS analysis highlights not only known interactions consistently identified within APC/C complexes, regardless of phosphorylation status, but also dynamic IDR-mediated interactions that are lost upon phosphorylation or are phosphorylation-dependent. Additionally, the data indicate that phosphorylation significantly reduces Apc1-300L's interaction with Apc8-L (IDR in Apc8) and Apc6, suggesting Apc1-300L's dislocation from the co-activator Cdc20 binding site, thereby facilitating Cdc20 loading onto the APC/C.
2024-04-23 | PXD050097 | Pride
Project description:Cdh1p is one of the two substrate adaptor proteins of the anaphase promoting complex/cyclosome (APC/C), an ubiquitin ligase that regulates proteolysis during cell cycle. In this work, using a proteomic approach, we found 135 mitochondrial proteins whose abundance was significantly altered in the cdh1Δ mutant, with 43 up-regulated proteins and 92 down-regulated proteins. When considering the group of significantly up-regulated proteins, these included subunits of the mitochondrial respiratory chain, enzymes from the TCA cycle and regulators of mitochondrial organization, suggesting a metabolic remodelling towards an increase in mitochondrial respiration. In accordance, mitochondrial oxygen consumption and COX activity increased in the absence of Cdh1p. These effects seem to be mediated by the transcriptional activator Yap1p, a major regulator of the yeast oxidative stress response. YAP1 deletion suppressed the increased Cyc1p levels and mitochondrial respiration in cdh1Δ cells. In agreement, Yap1p is transcriptionally more active in cdh1Δ cells, and responsible for the cdh1Δ mutant higher oxidative stress tolerance. Overall, our results unveil a new role for APC/C-Cdh1p in the regulation of the mitochondrial metabolic remodelling trough Yap1p activity.
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Project description:Signal transduction by Small Ubiquitin-like Modifier (SUMO) regulates a myriad of nuclear processes. Here, we report on the role of SUMO in mitosis in human cell lines. Knocking down the SUMO conjugation machinery resulted in a delay in mitosis and defects in mitotic chromosome separation. Searching for relevant SUMOylated proteins in mitosis, we identified the APC/C complex, a master regulator of metaphase to anaphase transition, as a SUMO target. The APC4 subunit is the major SUMO target in the complex, containing SUMO acceptor lysines at positions 772 and 798. SUMOylation increased APC/C ubiquitylation activity towards a subset of its targets, including the newly identified target KIF18B. Intriguingly, SUMOylation of APC/C was regulated by casein kinase driven phosphorylation of serines at positions 777 and 779. Combined, our findings demonstrate the importance of SUMO signal transduction for genome integrity during mitotic progression and reveal a triad of PTMs, cooperating to drive mitosis.
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Project description:The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that controls progression through the eukaryotic cell cycle by targeting key substrates for degradation through the ubiquitin proteasome pathway. During G1, the APC/C works in concert with its co-activator Cdh1 to recognize and ubiquitinate specific substrates during this phase of the cell cycle. While many APC/CCdh1 substrates play a role cell cycle regulation, others are involved in distinct cellular processes, indicating that diverse biological pathways are subject to APC/C-mediated control. To identify novel pathways and substrates regulated by APC/CCdh1, we conducted an unbiased proteomic screen in G1-arrested RPE1 cells acutely treated with small molecule APC/C inhibitors. Combining these results with degron prediction analysis, we discovered a range of putative APC/C substrates. We validated IRS2, a key adaptor protein involved in signaling downstream of the insulin and IGF1 receptors, as a novel direct APC/CCdh1 target. We demonstrate that genetic deletion of IRS2 reduces the expression of proteins involved in cell division and functionally impairs the spindle assembly checkpoint. Together, these findings reveal a novel connection between the insulin/IGF1 signaling network and the cell cycle regulatory machinery.
2020-06-22 | PXD018329 | Pride
Project description:Piwi proteins are a subfamily of Argonaute proteins that maintain germ cells in eukaryotes. However, the role of their human homologues in cancer stem cells and more broadly in cancer is poorly understood. Here, we report that the Piwi-like family members, including Piwil1 (Hiwi), are overexpressed in glioblastoma (GBM), with Piwil1 levels most frequently elevated. Piwil1 is enriched in glioma stem cells (GSCs) and helps to maintain their self-renewal. GSCs were transduces with control non-targeting shRNAs (shNT) and shPiwil1 (#1 and #2) and global gene expression was analyzed to identify Piwil1 downscream singalings.
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Project description:Coordination between sister chromatid separation and segregation is crucial for accurate chromosome partitioning to the offspring. Key to this process is the ability of mitotic spindle microtubules to respond to different molecular signals and remodel their dynamics accordingly. Based on their function, spindle microtubules are conventionally divided into three classes: kinetochore, interpolar and astral microtubules (kMTs, iMTs and aMTs, respectively). While different mechanisms have been proposed to control kMT and iMT dynamics, aMT regulation remains elusive. We here show that aMT dynamics are tightly regulated. aMTs remain unstable up to metaphase to control spindle orientation and are stabilized at anaphase onset. Necessary and sufficient for this stabilization is the degradation of the mitotic cyclin Clb4 mediated by the Anaphase Promoting Complex in combination with its activator subunit Cdc20 (APC/CCdc20). Our results contribute to delineate a comprehensive picture of late mitotic events, where individual steps of the signalling cascade initiated by APC/CCdc20 activation and culminating in cohesin cleavage time the final stages of mitosis by sequentially modulating the dynamics of the three classes of spindle microtubules.
2022-10-19 | PXD028828 | Pride
Project description:Genome haploidization at meiosis depends on two consecutive nuclear divisions, which are controlled by an oscillatory system consisting of Cdk1-cyclin B and the APC/C bound to the Cdc20 activator. How the oscillator generates exactly two divisions has been unclear. We have studied this question in yeast where exit from meiosis involves accumulation of the APC/C activator Ama1 at meiosis II. We show that inactivation of the meiosis I-specific protein Spo13/MEIKIN results in a single-division meiosis due to premature activation of APC/CAma1. In the wild-type, Spo13 bound to the polo-like kinase Cdc5 prevents Ama1 synthesis at meiosis I by stabilizing the translational repressor Rim4. In addition, Cdc5-Spo13 inhibits the activity of Ama1 by converting the B-type cyclin Clb1 from a substrate to an inhibitor of Ama1. Cdc20-dependent degradation of Spo13 at anaphase I unleashes a feedback loop that increases Ama1’s synthesis and activity, leading to irreversible exit from meiosis at the second division. Thus, by repressing the exit machinery at meiosis I, Cdc5-Spo13 ensures that cells undergo two divisions to produce haploid gametes.
2023-09-03 | PXD044597 | Pride
Project description:Tissue development and homeostasis rely on the proliferation of progenitor cells, whose identities are established by tightly controlled gene expression networks. However, mRNA synthesis is inhibited during mitosis, and the transcriptional programs that define a cell type must be restarted upon entry into each new cell cycle; how this is accomplished is poorly understood. Here, we identified a ubiquitin-dependent mechanism that integrates gene expression with cell division to preserve cell identity. We found that WDR5 and TBP, which bind active promoters during interphase, recruit the E3 ligase anaphase-promoting complex (APC/C) to specific transcription start sites during mitosis. This allows the APC/C to locally decorate histones with K11/K48-linked ubiquitin chains, which destabilizes nucleosomes and ensures continued gene expression in the next cell cycle. Mitotic exit and transcription re-initiation are therefore controlled by the same essential regulator, the APC/C, which provides a robust mechanism to maintain cell identity through cell division.
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