Lack of dominant-negative activity for tumor-related ZNRF3 missense mutations at endogenous levels DOI Creative Commons

Shanshan Li,

Jiahui Niu, Ruyi Zhang

и другие.

Oncogene, Год журнала: 2024, Номер unknown

Опубликована: Дек. 14, 2024

Abstract ZNRF3, a negative regulator of β-catenin signaling, removes Wnt receptors from the membrane. Currently, it is unknown which tumor-associated variants can be considered driver mutations and through mechanisms they contribute to cancer. Here we show that all truncating analyzed at endogenous levels exhibit loss-of-function, with longer retaining partial activity. Regarding missense mutations, 27/82 ZNRF3 in RING R-Spondin domain structures, lead (partial) loss-of-function/hyperactivation. Mechanistically, defective appear undergo endoplasmic-reticulum-associated degradation due protein misfolding, leading reduced levels. They fail reach membrane correctly, partially restored for several by culturing cells 27 °C. Although RNF43/ZNRF3 are often possess dominant-negative oncogene-like activity cancers, our findings challenge this notion. When representative heterozygously introduced into their impact on signaling mirrors heterozygous knockout, suggesting supposed effect non-existent. In other words, so-called “hyperactivating” ZNRF3/RNF43 behave as classical loss-of-function

Язык: Английский

Ubiquitination of transcription factors in cancer: unveiling therapeutic potential DOI Creative Commons
Dongha Kim, Hye Jin Nam, Sung Hee Baek

и другие.

Molecular Oncology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 14, 2025

Transcription factors, pivotal in gene expression regulation, are essential cancer progression. Their function is meticulously regulated by post‐translational modifications, including ubiquitination. This process, which marks proteins for degradation, can either enhance or inhibit the of transcription contingent on context. In cancers, dysregulated ubiquitination factors contributes to hallmark uncontrolled growth and survival tumors. For example, tumor suppressors such as p53 might be degraded prematurely due abnormal ubiquitination, causing genomic instability. On other hand, oncogenic may gain stability via thus facilitating tumorigenesis. Targeting ubiquitin–proteasome system (UPS) therefore could a viable therapeutic approach cancer. Emerging treatments aim block stabilize suppressors. review underscores critical impact factor‐altered Additionally, it outlines innovative approaches that involve inhibitors drugs directed at specific ubiquitin E3 ligases deubiquitinases (DUBs) regulate factor activity.

Язык: Английский

Процитировано

0
Lack of dominant-negative activity for tumor-associated ZNRF3 missense mutations at endogenous expression levels DOI Creative Commons
Shanshan Li, Jiahui Niu, Ruyi Zhang

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 16, 2024

Abstract ZNRF3, a negative regulator of β-catenin signaling, removes Wnt receptors from the membrane. Currently, it is unknown which tumor-associated variants can be considered driver mutations and through mechanisms they contribute to cancer. Here we show that all truncating analyzed at endogenous levels exhibit loss-of-function, with longer retaining partial activity. Regarding missense mutations, 27/82 ZNRF3 in RING R-Spondin domain structures, lead (partial) loss-of-function/hyperactivation. Mechanistically, defective R-spondin appear undergo endoplasmic-reticulum-associated degradation due protein misfolding. They reduced stability fail reach membrane correctly, partially restored for several by culturing cells 27°C. Although RNF43/ZNRF3 are often possess dominant-negative oncogene-like activity cancers, our findings challenge this notion. When representative heterozygously introduced into their impact on signaling mirrors heterozygous knockout, suggesting supposed effect non-existent. In other words, so-called “hyperactivating” ZNRF3/RNF43 behave as classical loss-of-function levels. Taken together, provide valuable information mutation tumorigenesis clarify mechanism action.

Язык: Английский

Процитировано

1
New Target(s) for RNF43 Regulation: Implications for Therapeutic Strategies DOI Open Access
Jeetendra Kumar Nag, Priyanga Appasamy, Hodaya Malka

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(15), С. 8083 - 8083

Опубликована: Июль 24, 2024

Cancer cells depend on specific oncogenic pathways or present a genetic alteration that leads to particular disturbance. Still, personalized and targeted biological therapy remains challenging, with current efforts generally yielding disappointing results. Carefully assessing onco-target molecular can, however, potently assist such for the selection of patient populations would best respond given drug treatment. RNF43, an E3 ubiquitin ligase negatively regulates Wnt/frizzled (FZD) receptors by their ubiquitination, internalization, degradation, controls key pathway in cancer. Recently, additional target proteins RNF43 were described, including p85 PI3K/AKT/mTOR signaling protease-activated receptor 2 (PAR2), G-protein-coupled induces β-catenin stabilization, independent Wnts. mutations impaired activity found several types cancers (e.g., gastrointestinal system tumors endometrial ovarian cancer), pointing high dependency FZD possibly PAR2 pathway. The development drugs toward these targets is essential improved treatment cancer patients.

Язык: Английский

Процитировано

1
RNF43 and ZNRF3: Versatile regulators at the membrane and their role in cancer DOI Creative Commons
Shanshan Li, Jiahui Niu, Ron Smits

и другие.

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2024, Номер unknown, С. 189217 - 189217

Опубликована: Ноя. 1, 2024

Язык: Английский

Процитировано

1
Lack of dominant-negative activity for tumor-related ZNRF3 missense mutations at endogenous levels DOI Creative Commons

Shanshan Li,

Jiahui Niu, Ruyi Zhang

и другие.

Oncogene, Год журнала: 2024, Номер unknown

Опубликована: Дек. 14, 2024

Abstract ZNRF3, a negative regulator of β-catenin signaling, removes Wnt receptors from the membrane. Currently, it is unknown which tumor-associated variants can be considered driver mutations and through mechanisms they contribute to cancer. Here we show that all truncating analyzed at endogenous levels exhibit loss-of-function, with longer retaining partial activity. Regarding missense mutations, 27/82 ZNRF3 in RING R-Spondin domain structures, lead (partial) loss-of-function/hyperactivation. Mechanistically, defective appear undergo endoplasmic-reticulum-associated degradation due protein misfolding, leading reduced levels. They fail reach membrane correctly, partially restored for several by culturing cells 27 °C. Although RNF43/ZNRF3 are often possess dominant-negative oncogene-like activity cancers, our findings challenge this notion. When representative heterozygously introduced into their impact on signaling mirrors heterozygous knockout, suggesting supposed effect non-existent. In other words, so-called “hyperactivating” ZNRF3/RNF43 behave as classical loss-of-function

Язык: Английский

Процитировано

1