NFX1, Its Isoforms and Roles in Biology, Disease and Cancer

Abstract

In 1989, two NFX1 protein products were identified as nuclear proteins with the ability to bind to X-box cis-elements. Since that publication, the NFX1 gene and its homologs have been identified, from yeast to humans. This review article summarizes what is known about the NFX1 gene across species. We describe the gene and protein motifs of NFX1 homologs and their functions in cellular biology, then turn to NFX1 in human biology and disease development. In that, we focus on more recent literature about NFX1 and its two splice variants protein products (NFX1-91 and NFX1-123) that are expressed in epithelial cells. We describe new evidence of conserved protein motifs, direct and indirect gene expression regulation, and critical protein-protein interactions. Finally, we stress the emerging roles of these NFX1 splice variants in high-risk human papillomavirus-associated cancers, and the increased expression of the longer splice variant, NFX1-123, found in these cancers.

Cervical Cancer Development: Implications of HPV16 E6E7-NFX1-123 Regulated Genes

“…Gene ontology analysis by GOrilla identified a significant enrichment in genes involved in protein binding and RNA binding ( Figure 1 B). These data are consistent with known functions of NFX1 [ 14 , 17 , 21 ]. These data support that, in the context of cervical cancer, NFX1 expression correlates with other genes and pathways involved in RNA biology and, by extension, may directly or indirectly regulate RNA expression and protein amounts of genes important in cervical cancer.…”

“…Our lab and others have shown that HPV16 E6 (16E6) binds to the host cell protein NFX1 [ 16 , 17 ], of which there are two isoforms: NFX1-91 and NFX1-123 [ 16 ]. The longer splice variant, NFX1-123, is highly expressed in cervical cancers and cell lines [ 18 , 19 , 20 ] and is upregulated in HPV+ compared to HPV- head and neck primary tumors [ 21 ]. It has also been shown that the protein partnership between 16E6 and NFX1-123 dysregulates genes involved in cellular growth, longevity, differentiation, and immune signaling [ 17 , 19 , 22 , 23 , 24 , 25 ].…”

High expression of NFX1‐123 in HPV positive head and neck squamous cell carcinomas

“…22 A recent review on NFX1 and its isoforms NFX1-123 and NFX1-91 highlighted the functional significance of NFX1-123 in human diseases and cancer. 23 We have recently confirmed that many genes upregulated by NFX1-123 and 16E6 in primary human foreskin keratinocytes (HFKs) were also overexpressed in cervical cancers when compared to the normal cervix. 17 This indicates that NFX1-123 plays a functional role in cervical cancer, and it also suggests that NFX1-123 may be important in HPV+ cancers at other anatomic sites.…”

“…NFX1‐123 also functions directly to augment JNK signaling in keratinocytes, increasing cellular differentiation markers and late HPV gene expression that is triggered by cellular differentiation, all while supporting continued cellular growth 22 . A recent review on NFX1 and its isoforms NFX1‐123 and NFX1‐91 highlighted the functional significance of NFX1‐123 in human diseases and cancer 23 . We have recently confirmed that many genes upregulated by NFX1‐123 and 16E6 in primary human foreskin keratinocytes (HFKs) were also overexpressed in cervical cancers when compared to the normal cervix 17 .…”

Post-Transcriptional Gene Regulation by HPV 16E6 and Its Host Protein Partners

“…This highlights a potential relationship of NFX1-123 with other HPV types, and additional studies are needed to identify those partnerships. These future studies are important because NFX1-123 is highly expressed in several HPV-associated cancers [ 46 , 47 , 48 ], because homologs of the NFX1 gene are found in yeast, plants, and multiple animal species, and because NFX1 functions in metabolism, stress tolerance, and the immune system, and has known functions in cell survival, metabolism, gene expression, and protein modifications [reviewed in 46].…”