Identification of novel E2F1 target genes regulated in cell cycle-dependent and independent manners

Iwanaga, Ritsuko; Komori, Hideyuki; Ishida, Susumu; Okamura, N; Nakayama, Keiko; Nakayama, Keiichi I.; Ohtani, Kiyoshi

doi:10.1038/sj.onc.1209210

Cited by 63 publications

(80 citation statements)

References 36 publications

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“…44 RAD51AP1 is an S phase cell cycle checkpoint gene that has recently been found to be directly induced by E2F1. 45 The overexpression of RAD51AP1 further supports the idea that dysregulation of E2F inducible transcripts occurs in HPV-positive SCCHN due to the inactivation of pRB by E7 expression. PRSS3 is a member of the serine protease family that shares significant homology with trypsinogen 1 and 2 and has been classified as a tumour suppressor gene in several types of cancers such as esophageal squamous cell carcinomas, gastric adenocarcinomas and non-small cell lung cancers.…”

Section: Discussionsupporting

confidence: 52%

Identification of differentially expressed genes in HPV-positive and HPV-negative oropharyngeal squamous cell carcinomas

Martínez

Wang

Hobson

et al. 2007

European Journal of Cancer

174

138

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Human papillomaviruses (HPVs) have been implicated in the pathogenesis of a subset of squamous cell carcinoma of the head and neck (SCCHN). The goal of this study was to compare the cellular gene expression profiles of HPV-positive and HPV-negative oropharyngeal carcinomas with those of the normal oral epithelium. Using Affymetrix Human U133A GeneChip, our results showed that 397 genes were differentially expressed in HPV-positive SCCHN compared to the normal oral epithelium. The up-regulated genes included those involved in cell cycle regulation (CDKN2A), cell differentiation (SFRP4) and DNA repair (RAD51AP1), while the down-regulated genes included those involved in proteolysis (PRSS3). We also found 162 differentially expressed genes in HPVnegative SCCHN compared to the normal oral mucosa. The up-regulated genes included those involved in cell proliferation (AKR1C3) and transcription regulation (SNAPC1), while downregulated genes included those involved in apoptosis (CLU) and RNA processing (RBM3). Our studies also identified a subgroup of 59 differentially expressed genes in HPV-positive SCCHN as compared to both HPV-negative SCCHN and normal oral tissues. Such up-regulated genes included those involved in nuclear structure and meiosis (SYCP2), DNA repair (RFC5), and transcription regulation (ZNF238). Genes involved in proteolysis (KLK8) and signal transduction (CRABP2) were found to be down-regulated in HPV-positive SCCHN. The results of GeneChip experiments were validated by quantitative real-time RT-PCR analysis of a few representative genes. Our results reveal specific gene expression patterns in HPV-positive and HPV-negative oropharyngeal squamous carcinomas that may serve as potential biomarkers for the development of SCCHN. Novelty and impact of the paper: Using a 22,200 human transcript oligonucleotide microarray platform, we have examined the gene expression profiles in HPV-positive and HPV-negative oropharyngeal squamous cell carcinomas as compared to the normal oropharyngeal mucosa. Our study has identified several new genes whose expression is specifically associated with the presence of HPV-16 in the oropharyngeal squamous mucosa. Furthermore, we have identified several genes whose expression is altered in HPVnegative SCCHN as compared to the normal oral mucosa. Results of our study could contribute to the understanding of pathogenic mechanisms involved in the development of HPV-positive and HPV-negative oropharyngeal cancers and consequently in the identification of potential biomarkers associated with these two subtypes of squamous cell carcinomas.

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Section: Discussionsupporting

confidence: 52%

Identification of differentially expressed genes in HPV-positive and HPV-negative oropharyngeal squamous cell carcinomas

Martínez

Wang

Hobson

et al. 2007

European Journal of Cancer

174

138

View full text Add to dashboard Cite

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“…77 Much to our surprise, many of the genes identified through the microarray included genes with known or hypothesized roles in neuronal migration, including, neogenin, a gene identified as a novel E2F target gene capable of activation in a cell cycle independent manner. 71 Finally, as we observe that both E2F1 and 3 are capable of regulating neural precursor proliferation through Rb, yet only E2F3 is capable of mediating migration, our data demonstrate that proliferation and migration can be mechanistically dissociated. Thus these data, which demonstrate specific roles for E2F3 in mediating cell cycle independent functions through Rb, represent the first physiological demonstration that in vivo roles for the Rb/E2F pathway beyond cell cycle regulation exist.…”

Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 79%

“…Finally, using a distinct approach where genes induced by E2F1 are identified based on subtraction screening, separate groups of genes were identified in response to serum stimulation. 71 Whereas E2F1 expression coupled with serum stimulation induced genes with roles in cell cycle progression, DNA replication, and apoptosis, E2F1 was also capable of directly inducing genes outside of serum stimulation, suggestive of atypical cell cycle independent targets. 71 Of these cell cycle independent E2F targets, many have known roles in development and differentiation.…”

Section: In Vitro Evidence For Function Beyond Cell Cycle Regulationmentioning

confidence: 99%

“…71 Whereas E2F1 expression coupled with serum stimulation induced genes with roles in cell cycle progression, DNA replication, and apoptosis, E2F1 was also capable of directly inducing genes outside of serum stimulation, suggestive of atypical cell cycle independent targets. 71 Of these cell cycle independent E2F targets, many have known roles in development and differentiation. 71 Thus together these data provide evidence that our scope of E2F function should be expanded to include regulation beyond the cell cycle, perhaps through atypical means.…”

Section: In Vitro Evidence For Function Beyond Cell Cycle Regulationmentioning

confidence: 99%

“…71 Of these cell cycle independent E2F targets, many have known roles in development and differentiation. 71 Thus together these data provide evidence that our scope of E2F function should be expanded to include regulation beyond the cell cycle, perhaps through atypical means.…”

Section: In Vitro Evidence For Function Beyond Cell Cycle Regulationmentioning

confidence: 99%

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Specific In Vivo Roles for E2Fs in Differentiation and Development

McClellan

Slack

2007

Cell Cycle

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E2Fs have been historically considered as key interacting factors for the retinoblastoma (Rb) family of pocket proteins, acting as universal regulators of cell cycle progression. Often exhibiting overlapping function, deregulated E2F activity is thought to lead to cancer or cell death. While early reports hypothesized that E2Fs may be capable of regulating distinct functions beyond proliferation, several recent reports have characterized increasingly diverse, context dependent functions for different E2Fs in vivo, often in what appears to be a manner beyond traditional cell cycle regulation. Ironically, many of these new functions are still mediated through the classical cell cycle regulatory Rb family of interacting factors. Here we review the recent advances, focusing on differentiation and development, to emphasize that E2F function is likely more complex than the simple model suggests, capable of exhibiting both specificity of function, and roles beyond cell cycle progression in vivo.

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Therapeutic Targeting of MZF1‐AS1/PARP1/E2F1 Axis Inhibits Proline Synthesis and Neuroblastoma Progression

et al. 2019

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Proline synthesis plays an important role in the metabolic reprogramming that contributes to tumor progression. However, the mechanisms regulating expression of proline synthetic genes in neuroblastoma (NB) remain elusive. Herein, through integrative screening of a public dataset and amino acid profiling analysis, myeloid zinc finger 1 (MZF1) and MZF1 antisense RNA 1 (MZF1‐AS1) are identified as transcriptional regulators of proline synthesis and NB progression. Mechanistically, transcription factor MZF1 promotes the expression of aldehyde dehydrogenase 18 family member A1 and pyrroline‐5‐carboxylate reductase 1, while proline facilitates the aggressiveness of NB cells. In addition, MZF1‐AS1 binds poly(ADP‐ribose) polymerase 1 (PARP1) to facilitate its interaction with E2F transcription factor 1 (E2F1), resulting in transactivation of E2F1 and upregulation of MZF1 and other oncogenic genes associated with tumor progression. Administration of a small peptide blocking MZF1‐AS1‐PARP1 interaction or lentivirus‐mediated short hairpin RNA targeting MZF1‐AS1 suppresses the proline synthesis, tumorigenesis, and aggressiveness of NB cells. In clinical NB cases, high expression of MZF1‐AS1, PARP1, E2F1, or MZF1 is associated with poor survival of patients. These results indicate that therapeutic targeting of MZF1‐AS1/PARP1/E2F1 axis inhibits proline synthesis and NB progression.

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Identification of novel E2F1 target genes regulated in cell cycle-dependent and independent manners

Cited by 63 publications

References 36 publications

Identification of differentially expressed genes in HPV-positive and HPV-negative oropharyngeal squamous cell carcinomas

Identification of differentially expressed genes in HPV-positive and HPV-negative oropharyngeal squamous cell carcinomas

Specific In Vivo Roles for E2Fs in Differentiation and Development

Therapeutic Targeting of MZF1‐AS1/PARP1/E2F1 Axis Inhibits Proline Synthesis and Neuroblastoma Progression

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