TRIM37 augments AP-2γ transcriptional activity and cellular localization via K63-linked polyubiquitination to drive breast cancer progression.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE182547 | GEO | 2022/07/25
REPOSITORIES: GEO
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Project description:Activator Protein 2 gamma (AP-2γ) is a master transcription factor that plays a critical role in the development and progression of breast cancer. However, the underlying mechanism is still unclear. Herein, using a proteomics approach, we identified Tripartite motif-containing 37 (TRIM37) as a novel coactivator of AP-2γ-mediated transcription in breast cancer cells. We demonstrate that TRIM37 facilitates AP-2γ chromatin binding to directly regulate the AP-2γ mediated transcriptional program. We also show that TRIM37 achieves this by stimulating K63 chain-linked ubiquitination of AP-2γ, promoting protein localization from the cytoplasm to the nucleus. In clinical analyses, we find TRIM37 is upregulated in multiple breast cancer datasets, supporting our findings that the TRIM37-AP-2γ interaction is essential for breast cancer tumor growth. Overall, our work reveals that TRIM37 is an oncogenic coactivator of AP-2γ in breast cancer and provides a novel therapeutic target for treating the disease.
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Project description:Using a proteomics approach, we identified the Tripartite Motif Containing 37 (TRIM37) as a novel transcriptional coactivator of AP-2γ. We demonstrate TRIM37 facilitates AP-2γ chromatin binding to regulate the AP-2γ mediated transcriptional program directly. We provide evidence that TRIM37 achieves this by stimulating K63-chain-linked polyubiquitination of AP-2γ, promoting protein localization from the cytoplasm to the nucleus. In clinical analyses, we find TRIM37 is upregulated in multiple breast cancer datasets, supporting our findings that TRIM37-AP-2γ interaction is essential for breast cancer tumor growth. Overall, our work revealed that TRIM37 is an oncogenic coactivator of AP-2γ in breast cancer and provides a novel therapeutic target for treating the disease.
2022-07-25 | GSE182546 | GEO
Project description:Using a proteomics approach, we identified the Tripartite Motif Containing 37 (TRIM37) as a novel transcriptional coactivator of AP-2γ. We demonstrate TRIM37 facilitates AP-2γ chromatin binding to regulate the AP-2γ mediated transcriptional program directly. We provide evidence that TRIM37 achieves this by stimulating K63-chain-linked polyubiquitination of AP-2γ, promoting protein localization from the cytoplasm to the nucleus. In clinical analyses, we find TRIM37 is upregulated in multiple breast cancer datasets, supporting our findings that TRIM37-AP-2γ interaction is essential for breast cancer tumor growth. Overall, our work revealed that TRIM37 is an oncogenic coactivator of AP-2γ in breast cancer and provides a novel therapeutic target for treating the disease.
2022-07-25 | GSE182545 | GEO
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Project description:Type I interferons (IFNs) exhibit strong antiviral activity and induce the expression of antiviral proteins. Since excessive expression of type I IFNs is harmful to the host, their expression should be turned off at the appropriate time. In this study, we find that post-translational modification of LGP2, a member of the RIG-I-like receptor family, modulates antiviral innate immune responses. The LGP2 protein undergoes K63-linked polyubiquitination in response to cytoplasmic double-stranded RNAs or viral infection. Our mass spectrometry analysis reveals the K residues ubiquitinated by the Riplet ubiquitin ligase. LGP2 ubiquitination occurs with a delay compared to RIG-I ubiquitination. Interestingly, ubiquitination-defective LGP2 mutations increase the expression of type I IFN at a late phase, whereas the mutant proteins attenuate other antiviral proteins, such as SP100, PML, and ANKRD1. Our data indicate that delayed polyubiquitination of LGP2 fine-tunes RIG-I-dependent antiviral innate immune responses at a late phase of viral infection.
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Project description:I?B kinase ? (IKK?, IKBKE) is a key regulator of innate immunity and a breast cancer oncogene, amplified in ~30% of breast cancers, that promotes malignant transformation through NF-?B activation. Here, we show that IKK? is modified and regulated by K63-linked polyubiquitination at lysine 30 and lysine 401. Tumor necrosis factor alpha and interleukin-1? stimulation induces IKK? K63-linked polyubiquitination over baseline levels in both macrophages and breast cancer cell lines, and this modification is essential for IKK? kinase activity, IKK?-mediated NF-?B activation, and IKK?-induced malignant transformation. Disruption of K63-linked ubiquitination of IKK? does not affect its overall structure but impairs the recruitment of canonical NF-?B proteins. A cIAP1/cIAP2/TRAF2 E3 ligase complex binds to and ubiquitinates IKK?. Altogether, these observations demonstrate that K63-linked polyubiquitination regulates IKK? activity in both inflammatory and oncogenic contexts and suggests an alternative approach to targeting this breast cancer oncogene.
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