SMAD4 activates Wnt signaling pathway to inhibit granulosa cell apoptosis
Open accessAbstract
The TGF-β and Wnt signaling pathways are interrelated in many cell types and tissues, and control cell functions in coordination. Here, we report that SMAD4, a downstream effector of the TGF-β signaling pathway, induces FZD4, a receptor of the Wnt signaling pathway, establishing a novel route of communication between these two pathways in granulosa cells (GCs). We found that SMAD4 is a strong inducer of FZD4, not only initiating FZD4 transcription but also activating FZD4-dependent Wnt signaling and GC apoptosis. Furthermore, we identified the direct and indirect mechanisms by which SMAD4 promotes expression of FZD4 in GCs. First, SMAD4 functions as a transcription factor to directly bind to the FZD4 promoter region to increase its transcriptional activity. Second, SMAD4 promotes production of SDNOR, a novel lncRNA that acts as a sponge for miR-29c, providing another mean to block miR-29c from degenerating FZD4 mRNA. Overall, our findings not only reveal a new channel of crosstalk between the TGF-β and Wnt signaling pathways, SMAD4–FZD4 axis, but also provide new insights into the regulatory network of GC apoptosis and follicular atresia. These RNA molecules, such as miR-29c and lnc-SDNOR, represent potential targets for treatment of reproductive diseases and improvement of female fertility.
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Dysregulation of SMAD4 is associated with cancer progression, encompassing autophagy, invasion and metastasis.
“Dysregulation of SMAD4 is associated with various aspects of cancer progression, encompassing autophagy, invasion and metastasis, underscoring its significance in cellular responses and disease [114].”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [114]
The Introduction (page not provided) says SMAD4 regulates autophagy, invasion and metastasis, and that its deficiency or inactivation can drive cancers. It does not specifically establish that dysregulation of SMAD4 affects all three as aspects of cancer progression. (LLM, conf=0.83)
Experimental — accuracy not yet measuredSMAD4 participates in crosstalk with the Wnt signaling pathway by inducing transcription of FZD4, a Wnt pathway receptor.
“Beyond the TGF-β pathway, SMAD4 participates in crosstalk with the Wnt signaling pathway by inducing the transcription of FZD4, a Wnt pathway receptor, emphasizing its broader regulatory impact on cellular functions [114].”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [114]
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- Authors
- Du, X., Li, Q., Yang, L., Liu, L., Cao, Q., & Li, Q.
- Affiliations
- Nanjing Agricultural University (CN)
- Corresponding author
- Li, Qifa
- Venue
- Cell Death & Disease
- Published
- 2020-05-15
- Volume
- 11
- Issue
- 5
- Pages
- 373-373
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC7228950
- OpenAlex
- W3024285751
- Cited by
- 76
- References
- 70
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 14 · 2023: 16 · 2022: 12 · 2021: 10 · 2020: 4
- FWCI
- 3.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (31630072, 31902130)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Keywords
- SMAD4, Wnt signaling, TGF-beta signaling, FZD4, granulosa cells, apoptosis, follicular atresia, long non-coding RNA, miR-29c, microRNA sponge, transcriptional regulation, female fertility
- MeSH terms
- Female, Follicular Atresia, Gene Expression Regulation, Granulosa Cells, Humans, Promoter Regions, Genetic, Apoptosis, MicroRNAs, Smad4 Protein, Wnt Signaling Pathway
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