GDNF-inducible zinc finger protein 1 is a sequence-specific transcriptional repressor that binds to the HOXA10 gene regulatory region
Open accessAbstract
The RET tyrosine kinase receptor and its ligand, glial cell line-derived neurotrophic factor (GDNF) are critical regulators of renal and neural development. It has been demonstrated that RET activates a variety of downstream signaling cascades, including the RAS/mitogen-activated protein kinase and phosphatidylinositol-3-kinase(PI3-K)/AKT pathways. However, nuclear targets specific to RET-triggered signaling still remain elusive. We have previously identified a novel zinc finger protein, GZF1, whose expression is induced during GDNF/RET signaling and may play a role in renal branching morphogenesis. Here, we report the DNA binding property of GZF1 and its potential target gene. Using the cyclic amplification and selection of targets technique, the consensus DNA sequence to which GZF1 binds was determined. This sequence was found in the 5' regulatory region of the HOXA10 gene. Electrophoretic mobility shift assay revealed that GZF1 specifically binds to the determined consensus sequence and suppresses transcription of the luciferase gene from the HOXA10 gene regulatory element. These findings thus suggest that GZF1 may regulate the spatial and temporal expression of the HOXA10 gene which plays a role in morphogenesis.
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HIC1, HIC2, GZF1, OSR1, OSR2, and SALL4 have all been implicated in development.
“HIC1, HIC2, GZF1, OSR1, OSR2, and SALL4 have all been implicated in development”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [29]
The Introduction (page unavailable) links GZF1 to renal branching morphogenesis, and the discussion of GZF1 and HOXA10 (page unavailable) considers a possible role in kidney development. The paper does not establish a developmental role for HIC1, HIC2, OSR1, OSR2, or SALL4; HIC1 appears only in references concerning transcriptional repression. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHIC1, HIC2, GZF1, OSR1, OSR2, and SALL4 could contribute to developmental abnormalities in fetuses exposed to thalidomide.
“and could contribute to developmental abnormalities in fetuses exposed to thalidomide (25–30).”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [29]
The section on GZF1 and the HOXA10 regulatory region proposes a possible role for GZF1 in normal kidney development. It does not address thalidomide exposure or fetal abnormalities, and it does not implicate the other five named genes in those abnormalities. (LLM, conf=0.82)
Experimental — accuracy not yet measuredSeveral ZFs identified as degraded in functional experiments, or in vitro binders that could be targeted with further drug development, have been implicated in human disease.
“Several of the ZFs identified as degraded in functional experiments, or in vitro binders that could be targeted with further drug development, have been implicated in human disease.”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [29]
The analysis of GZF1 zinc finger motifs reports DNA-binding experiments, but does not link GZF1 or several zinc finger proteins to human disease. A search for “human disease” found that phrase only in a reference about GDNF/RET signaling, not in a finding about the zinc finger proteins described in the claim. The copy also does not address their degradation or potential drug targeting. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN
Sievers, Q. L., Petzold, G., Bunker, R. D., Renneville, A., Słabicki, M., Liddicoat, B. J., Abdulrahman, W., Mikkelsen, T., Ebert, B. L., & Thomä, N. H. (2018) · Science · doi:10.1126/science.aat0572 · Cited by 537 · see citing works
- Authors
- Morinaga, T.
- Affiliations
- Nagoya University (JP)
- Corresponding author
- Morinaga, T.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-07-21
- Volume
- 33
- Issue
- 13
- Pages
- 4191-4201
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC1180748
- OpenAlex
- W2117778086
- Cited by
- 18
- References
- 42
- Citations by year
- 2026: 2 · 2024: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2018: 1 · 2017: 2 · 2016: 1
- FWCI
- 0.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- other-oa
- Locations
- Nucleic Acids Research (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Renal and related cancers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- zinc finger proteins, glial cell line-derived neurotrophic factor, RET receptor tyrosine kinase, HOXA10, transcriptional repressor, DNA binding, gene regulatory regions, transcriptional repression, consensus sequence
- MeSH terms
- Homeobox A10 Proteins, Animals, Base Sequence, Binding Sites, Cell Line, DNA Mutational Analysis, DNA-Binding Proteins, Humans, Molecular Sequence Data, Nuclear Proteins, Repressor Proteins, Transcription Factors, Zinc Fingers, Consensus Sequence, Homeodomain Proteins, Response Elements, Mice, Kruppel-Like Transcription Factors
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