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Tumorigenesis Suppressor Pdcd4 Down-Regulates Mitogen-Activated Protein Kinase Kinase Kinase Kinase 1 Expression To Suppress Colon Carcinoma Cell Invasion
Open accessAbstract
Programmed cell death 4 (Pdcd4) suppresses neoplastic transformation by inhibiting the activation of c-Jun and consequently AP-1-dependent transcription. We report that Pdcd4 blocks c-Jun activation by inhibiting the expression of mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1)/hematopoietic progenitor kinase 1, a kinase upstream of Jun N-terminal kinase (JNK). cDNA microarray analysis of Pdcd4-overexpressing RKO human colon carcinoma cells revealed MAP4K1 as the sole target of Pdcd4 on the JNK activation pathway. Cotransfection of a MAP4K1 promoter-reporter with Pdcd4 demonstrated inhibition of transcription from the MAP4K1 promoter. Ectopic expression of Pdcd4 in metastatic RKO cells suppressed invasion. MAP4K1 activity is functionally significant in invasion, as overexpression of a dominant negative MAP4K1 (dnMAP4K1) mutant in RKO cells inhibited not only c-Jun activation but also invasion. Overexpression of a MAP4K1 cDNA in Pdcd4-transfected cells rescued the kinase activity of JNK. Thus, Pdcd4 suppresses tumor progression in human colon carcinoma cells by the novel mechanism of down-regulating MAP4K1 transcription, with consequent inhibition of c-Jun activation and AP-1-dependent transcription.
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“PDCD4 was shown to inhibit the activation of c-Jun by suppressing the JNK-activation in avian QT6 cells [34] and to suppress the expression of the upstream kinase MAP4K1 in RKO human colon carcinoma cells [33].”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [33]
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Metadata
- Authors
- Yang, H.-S., Matthews, C. P., Clair, T., Wang, Q., Baker, A. R., Li, C.-C. H., Tan, T.-H., & Colburn, N. H.
- Affiliations
- National Cancer Institute (US)
- Department of Immunology, Bayer College of Medicine, Houston, Texas 77030
- Corresponding author
- Yang, Hsin-Sheng
- Colburn, Nancy H.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2006-02-01
- Volume
- 26
- Issue
- 4
- Pages
- 1297-1306
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1367180
- OpenAlex
- W2159430811
- Cited by
- 202
- References
- 52
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 2 · 2023: 1 · 2022: 6 · 2021: 9 · 2020: 10 · 2019: 6 · 2018: 8 · 2017: 10 · 2016: 12 · 2015: 12 · 2014: 13 · 2013: 18 · 2012: 14
- FWCI
- 5.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- University of Texas MD Anderson Cancer Center
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- PDCD4, MAP4K1, HPK1, JNK activation, c-Jun activation, AP-1 transcription, colon cancer, tumor invasion, metastasis, tumor suppressor, RKO cells
- MeSH terms
- Base Sequence, Cell Movement, Cloning, Molecular, Colonic Neoplasms, DNA, Neoplasm, Enzyme Activation, Extracellular Matrix, Humans, Neoplasm Invasiveness, Phosphorylation, Promoter Regions, Genetic, Transcription, Genetic, Transfection, Down-Regulation, RNA-Binding Proteins, Protein Serine-Threonine Kinases, Transcription Factor AP-1, Oligonucleotide Array Sequence Analysis, MAP Kinase Signaling System, Cell Line, Tumor, JNK Mitogen-Activated Protein Kinases, Apoptosis Regulatory Proteins
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