Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation
Open accessAbstract
An mRNA differential display comparison of mouse JB6 promotion-sensitive (P+) and -resistant (P−) cells identified a novel gene product that inhibits neoplastic transformation. The JB6 P+ and P− cells are genetic variants that differ in their transformation response to tumor promoters; P+ cells form anchorage-independent colonies that are tumorigenic, and P− cells do not. A differentially displayed fragment, A7-1 , was preferentially expressed in P− cells at levels ≥10-fold those in P+ cells, making its mRNA a candidate inhibitor of neoplastic transformation. An A7-1 cDNA was isolated that was identical to murine Pdcd4 gene cDNAs, also known as MA-3 or TIS , and analogous to human H731 and 197/15a . Until now, the function of the Pdcd4 protein has been unknown. Paralleling the mRNA levels, Pdcd4 protein levels were greater in P− than in P+ cells. Pdcd4 mRNA was also expressed at greater levels in the less progressed keratinocytes of another mouse skin neoplastic progression series. To test the hypothesis that Pdcd4 inhibits tumor promoter-induced transformation, stable cell lines expressing antisense Pdcd4 were generated from parental P− cells. The reduction of Pdcd4 proteins in antisense lines was accompanied by acquisition of a transformation-sensitive (P+) phenotype. The antisense-transfected cells were reverted to their initial P− phenotype by overexpression of a Pdcd4 sense fragment. These observations demonstrate that the Pdcd4 protein inhibits neoplastic transformation.
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Up-regulation of Pdcd4 in P+ type cells changes them to P- type cells.
“They showed that the down-regulation of Pdcd4 in P- cells resulted in acquisition of transformation sensitive phenotype (P+) and the up-regulation of Pdcd4 in the P+ type cells changed to P- type cells.”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [6]
The Discussion says the authors tried to test whether Pdcd4 overexpression would block transformation in P+ cells, but obtained no transfectants stably expressing Pdcd4. They therefore did not show that up-regulation changed P+ cells to P− cells. The sense-expression reversal described elsewhere in the Discussion was performed in antisense-treated P− cells, not the original P+ cells. (LLM, conf=0.90)
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Experimental — accuracy not yet measuredPdcd4 suppresses AP-1 activation and TPA-induced neoplastic transformation in JB6 cells.
“Experiments to find a suppressor of the neoplastic transformation induced by the tumor promotors resulted in Pdcd4 suppressing AP-1 activation and TPA-induced neoplastic transformation in the JB6 cells [6].”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [6]
The transformation experiments report that reducing Pdcd4 in JB6 cells permitted TPA-induced colony formation, while restoring Pdcd4 reduced that response (section “Decreasing the Endogenous Pdcd4 Protein Level Is Accompanied by”; page unavailable). The Discussion says Pdcd4 might control activation of AP-1, but presents this as a possible mechanism, not a demonstrated suppression of AP-1 activation. (LLM, conf=0.90)
Experimental — accuracy not yet measuredPDCD4 is a tumor suppressor induced by apoptotic stimuli that regulates both translation and transcription.
“PDCD4 is a tumor suppressor induced by apoptotic stimuli that regulates both translation and transcription.”
From Tumor suppressor PDCD4 inhibits NF-κB-dependent transcription in human glioblastoma cells by direct interaction with p65 (2014) · cites this paper as [2]
The Discussion reports that Pdcd4 inhibits tumor promoter-induced neoplastic transformation and that its gene was found to be up-regulated with apoptosis in several model systems. It only proposes that Pdcd4 might regulate gene expression through transcription factors; it does not establish transcriptional regulation. The passage mentioning translation concerns an effect of antisense RNA, not a translation-regulating function of Pdcd4. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPDCD4 downregulation stimulates TPA-induced transformation of cells.
“PDCD4 downregulation stimulates and PDCD4 upregulation inhibits the TPA-induced transformation of cells.”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [6]
PDCD4 upregulation inhibits TPA-induced transformation of cells.
“PDCD4 downregulation stimulates and PDCD4 upregulation inhibits the TPA-induced transformation of cells.”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [6]
In response to TPA, JB6 P+ cells form colonies in agar plates, but P- cells do not.
“In response to the tumor promotor TPA, P+ cells form colonies in agar plates, but P- cells do not.”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [6]
Pdcd4 expression is down-regulated in mouse JB6 promotion sensitive P+ cells compared to resistant P- cells.
“Cmarik et al. [6] reported that Pdcd4 expression is down-regulated in mouse JB6 promotion sensitive (P+) cells compared to resistant (P-) cells.”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [6]
Down-regulation of Pdcd4 in P- cells results in acquisition of transformation sensitive phenotype P+.
“They showed that the down-regulation of Pdcd4 in P- cells resulted in acquisition of transformation sensitive phenotype (P+) and the up-regulation of Pdcd4 in the P+ type cells changed to P- type cells.”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [6]
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Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions
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The role of Pdcd4 in tumour suppression and protein translation
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The transformation suppressor protein Pdcd4 shuttles between nucleus and cytoplasm and binds RNA
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“Frontiers in Cell and Developmental Biology | www.frontiersin.org 1 November 2020 | Volume 8 | Article 593685 Cmarik et al. (1999) reported that expression of PDCD4 is less in the mouse JB6 promotion-sensitive cells than that in promotionresistant cells, and it functions as an inhibitor of…”
BackgroundRegulation of tumor suppressor PDCD4 by novel protein kinase C isoforms
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Self-citation
- Authors
- Cmarik, J. L., Min, H., Hegamyer, G., Zhan, S., Kulesz-Martin, M., Yoshinaga, H., Matsuhashi, S., & Colburn, N. H.
- Affiliations
- Roswell Park Comprehensive Cancer Center (US)
- ORCID
- Kulesz-Martin, Molly
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1999-11-23
- Volume
- 96
- Issue
- 24
- Pages
- 14037-14042
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC24186
- OpenAlex
- W2055897952
- Cited by
- 254
- References
- 3
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 5 · 2023: 2 · 2022: 5 · 2021: 8 · 2020: 9 · 2019: 6 · 2018: 11 · 2017: 4 · 2016: 16 · 2015: 14 · 2014: 19 · 2013: 19 · 2012: 10
- FWCI
- 2.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01co056000-057, NO1-CO-56000, CO-56000)
- National Cancer Institute (N01 CO 56000, NO1CO56000)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- PDCD4, tumor suppressor, oncogenic transformation, tumor promoters, JB6 cells, skin carcinogenesis, keratinocytes, mRNA differential display, cDNA cloning, anchorage-independent growth
- MeSH terms
- Animals, Cell Line, Cell Transformation, Neoplastic, Humans, Mice, Inbred BALB C, Phenotype, Proteins, Rabbits, RNA, Messenger, Tetradecanoylphorbol Acetate, Protein Biosynthesis, Tumor Cells, Cultured, Immunoblotting, Keratinocytes, Gene Expression, RNA-Binding Proteins, Apoptosis Regulatory Proteins, Mice
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