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Regulatory function of Pja2 mediated by the P2rx3/P2rx7 axis in mouse hippocampal neuronal cells

ABSTRACT: A member of the growing family of mammalian RING E3-ubiquitin ligases praja2 (Pja2) was reported to function not only in several types of cancer but also in the neurological diseases and disorders. As a result, the expression of App, Mapt and Gsap could be inhibited by Pja2 overexpression and activated by the knockdown of Pja2. RNA sequencing (RNA-seq) was then used to evaluate and quantify the transcriptomes in response to the overexpression of Pja2 in mouse hippocampal neuronal HT-22 cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE109699 | GEO | 2020/04/25

REPOSITORIES: GEO

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Regulatory function of Pja2 mediated by the P2rx3/P2rx7 axis in mouse hippocampal neuronal cells

Project description:Praja2 (Pja2), a member of the growing family of mammalian RING E3 ubiquitin ligases, is reportedly involved not only in several types of cancer but also in neurological diseases and disorders. However, the underlying genetic mechanism of Pja2 regulation in the nervous system remains unclear. To study the cellular and molecular function of Pja2 in mouse hippocampal neuronal cells (MHNCs), we used gain- and loss-of-function manipulations of Pja2 in HT-22 cells and tested their regulatory effects on three Alzheimer's disease (AD) genes and cell proliferation. We found that the expression of AD markers including App, Mapt and Gsap could be inhibited by Pja2 overexpression and activated by Pja2 knockdown. In addition, HT-22 cell proliferation was enhanced by Pja2 upregulation and suppressed by its downregulation. We also applied RNA-Seq to evaluate and quantify the targets that responded to the enforced expression of Pja2. In particular, P2rx3 and P2rx7, which have different expression patterns in the critical calcium signaling pathway, were shown to mediate the regulatory effect of Pja2 in HT-22 cells. Functional studies indicated that Pja2 regulated HT-22 cell development and AD marker genes by inhibiting P2rx3 but promoting P2rx7, a gene downstream of P2rx3. In conclusion, our results provide new insights into the regulatory function of the gene Pja2 in MHNCs, underscoring the potential relevance of this molecule to the pathophysiology of AD.

2020-12-15 | E-MTAB-6464 | biostudies-arrayexpress

The Hace1 E3 Ligase Modulates the Activity of Multiple Tumor Suppressive CRL E3 Ligases by binding to CAND1

Project description:The Hace1 E3 ligase is a tumor suppressor in stressed cells. Through unknown mechanisms, Hace1 indirectly targets the cyclin D1 proto-oncogene for proteasomal degradation during nutrient depletion. We now show that Hace1 targets HIF1alpha for VHL-dependent degradation during hypoxia. To better understand these diverse actions we performed mass spectrometry to identify Hace1-interacting proteins. We show that Hace1 interacts with cullin-associated NEDD8-dissociated protein 1 (CAND1) under nutrient depletion and hypoxia. CAND1 binds cullins and prevents their entry into cullin ring E3 ligase (CRL) complexes, thus blocking CRL activity. Hace1 binding releases CUL1/2 from CAND1, facilitating assembly of CRL complexes to degrade cyclin D1 and HIF1alpha, respectively. These findings suggest a broad role for Hace1 in regulating tumor suppressive CRL E3 ligases. In this study, we used gene expression profiling to characterize how Hace1 overexpression affect the transcriptional response to hypoxic stress Using Affymetrix exon-level microarrays, we compared the expression profile of HEK293 cells overexpressing either Hace1 or MSCV vector alone, under hypoxia or normoxia

2011-07-01 | E-GEOD-25452 | biostudies-arrayexpress

The Hace1 E3 Ligase Modulates the Activity of Multiple Tumor Suppressive CRL E3 Ligases by binding to CAND1

2011-07-01 | GSE25452 | GEO

The p53-dependent role of JAB1 in OS pathogenesis

Project description:JAB1 is a regulator of ubiquitin mediated protein degradation upstream of the 26S proteasome. JAB1 regulates the ubiquitin proteasome system through controlling the activity of the largest family of E3 ubiquitin ligases, the Cullin-RING Ligases. JAB1 is also a transcriptional co-factor contolling the expression of numerous genes and regulates musculoskeletal development in vivo. It is reported that JAB1 is overexpressed in many cancers, making it a potential oncogene. Thus, JAB1 has a highly spatiotemporal specific role in development and cancer pathogenesis. This study aims to determine the JAB1-mediated transcriptome that exists in osteosarcoma cells.

2020-06-10 | GSE117773 | GEO

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Dual BACH1 regulation by complementary SCF-type E3 ligases

Project description:BACH1, FBXO22, FBXL17, oxidative stress response, E3, Cullin-RING ligases, F-box, cysteine modification, S-nitrosylation, heme

2024-12-03 | PXD051074 | Pride

Functional genomics identify distinct and overlapping genes mediating resistance to different classes of heterobifunctional degraders of oncoproteins

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Quantitative XL-MS Analysis of HHARI in the presence or absence of 4EHP

Project description:RING-Between-RING (RBR) E3 ligases mediate ubiquitin transfer through an obligate E3- ubiquitin thioester intermediately prior to substrate ubiquitination. While RBRs share a conserved catalytic module, substrate recruitment mechanisms remain enigmatic and the relevant domains have yet to be identified for any member of the class. Here we characterize the interaction between the auto-inhibited RBR, HHARI (AriH1), and its target protein, 4EHP, using quantitative XL-MS.

2024-07-26 | PXD030871 | panorama

E2-RING expansion of the NEDD8 cascade confers specificity to cullin modification

Project description:Ubiquitin and ubiquitin-like proteins (UBLs) are directed to targets by cascades of E1, E2, and E3 enzymes. The largest ubiquitin E3 subclass consists of cullin-RING ligases (CRLs), which contain one each of several cullins (CUL1, -2, -3, -4, or -5) and RING proteins (RBX1 or -2). CRLs are activated by ligation of the UBL NEDD8 to a conserved cullin lysine. How is cullin NEDD8ylation specificity established? Here we report that, like UBE2M (also known as UBC12), the previously uncharacterized E2 UBE2F is a NEDD8-conjugating enzyme in vitro and in vivo. Biochemical and structural analyses indicate how plasticity of hydrophobic E1-E2 interactions and E1 conformational flexibility allow one E1 to charge multiple E2s. The E2s have distinct functions, with UBE2M/RBX1 and UBE2F/RBX2 displaying different target cullin specificities. Together, these studies reveal the molecular basis for and functional importance of hierarchical expansion of the NEDD8 conjugation system in establishing selective CRL activation. Mol Cell 33:483-495, 2009. Keywords: Comparison of gene expression profiles

2009-03-24 | GSE14088 | GEO

A Genome-wide Gene Expression Analysis and Database in Transgenic Mice during Development of Amyloid or Tau Pathology

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