Alternative titles; symbols
HGNC Approved Gene Symbol: TFDP1
Cytogenetic location: 13q34 Genomic coordinates (GRCh38) : 13:113,584,688-113,641,473 (from NCBI)
The E2F transcription factor family (see 189971) regulates the expression of various cellular promoters, particularly those involved in the cell cycle. E2F factors bind to DNA as homodimers or heterodimers in association with dimerization partner DP1. TFDP1 may be the first example of a family of related transcription factors; see TFDP2 (602160).
The cDNA for transcription factor DP1 (TFDP1) was cloned by Girling et al. (1993) from a library of F9 embryonal carcinoma cells by using PCR primers predicted from partial peptide sequences of a 46-kD protein. The protein was isolated by virtue of its binding to a DNA sequence taken from the adenovirus E2A promoter. TFDP1 is a component of the DRTF1/E2F transcription factor complex, which coordinates events in the cell cycle by interacting with RB1 (614041), the retinoblastoma gene product, and RB-related proteins (Bandara and La Thangue, 1991). DRTF1 activity is downregulated in differentiating embryonal carcinoma cells, and E2F activity is induced in adenovirus-infected HeLa cells. Bandara and La Thangue (1991) showed that the adenovirus E1a protein causes the dissociation of the RB protein from this complex. TFDP1 has a predicted sequence of 410 amino acids (Girling et al., 1993) with a region of similarity to E2F1 (189971), accounting for the ability of both to bind the same DNA sequence.
SMAD3 (603109) is a direct mediator of transcriptional activation by the TGF-beta (190180) receptor (see 190181). Its target genes in epithelial cells include cyclin-dependent kinase (CDK; see 116953) inhibitors that generate a cytostatic response. Chen et al. (2002) defined how, in the same context, SMAD3 can mediate transcriptional repression of the growth-promoting gene MYC (190080). A complex containing SMAD3, the transcription factors E2F4 (600659), E2F5 (600967), and DP1, and the corepressor p107 (116957) preexists in the cytoplasm. In response to TGF-beta, this complex moves into the nucleus and associates with SMAD4 (600993), recognizing a composite SMAD-E2F site on MYC for repression. Previously known as the ultimate recipients of CDK regulatory signals, E2F4/E2F5 and p107 act here as transducers of TGF-beta receptor signals upstream of CDK. SMAD proteins therefore mediate transcriptional activation or repression depending on their associated partners.
Gain-of-function mutations in LRRK2 (609007) cause Parkinson disease (PARK8; 607060) characterized by age-dependent degeneration of dopaminergic neurons. Gehrke et al. (2010) found that LRRK2 interacted with the microRNA (miRNA) pathway to regulate protein synthesis. They showed that mRNAs for Drosophila E2f1 and Dp, which had previously been implicated in cell cycle and survival control (Girling et al., 1993), were translationally repressed by the miRNAs Let7 (MIRLET7A1; 605386) and miR184* (613146), respectively. Pathogenic human LRRK2 antagonized Let7 and miR184*, leading to overproduction of E2f1 and Dp, which was critical for LRRK2 pathogenesis. In Drosophila, genetic deletion of Let7, antagomir-mediated blockage of Let7 and miR184* action, transgenic expression of Dp target protector, or replacement of endogenous Dp with a Dp transgene nonresponsive to Let7 each had toxic effects similar to those of pathogenic LRRK2. Conversely, increasing the level of Let7 or miR184* attenuated pathogenic LRRK2 effects. Human LRRK2 associated with Drosophila Argonaute-1 (EIF2C1, or AGO1; 606228) or human Argonaute-2 (EIF2C2, or AGO2; 606229) of the RNA-induced silencing complex (RISC). In aged fly brain, Ago1 protein level was negatively regulated by human LRRK2. Furthermore, pathogenic LRRK2 promoted the association of phosphorylated 4EBP1 (EIF4EPB1; 602223) with human AGO2. Gehrke et al. (2010) concluded that deregulated synthesis of E2F1 and DP caused by miRNA pathway impairment is a key event in LRRK2 pathogenesis, suggesting that novel miRNA-based therapeutic strategies may be useful for Parkinson disease.
In a study mapping the human SOX1 gene (602148) to 13q34 by fluorescence in situ hybridization, Malas et al. (1997) demonstrated that the TFDP1 gene maps distal to SOX1 on 13q34. Zhang et al. (1997) used fluorescence in situ hybridization to map the TFDP1 gene to human chromosome 13q34. They noted the presence of a pseudogene, termed TFDP1P, at 1q32.3.
Abba et al. (2007) observed genomic amplification affecting the murine chromosome 8 region in mouse mammary tumors. The homologous syntenic cluster mapping to human chromosome 13q34 was also amplified in a subset of human breast cancers. Specifically, the TFDP1 gene showed the highest frequency of amplification affecting 23 (31.1%) of 74 primary breast cancer samples. Other genes within the same cluster region on 13q34 were also amplified, including CUL4A (603137), LAMP1 (153330), and GAS6 (600441). Metaanalysis of publicly available gene expression data showed a strong association between high expression of TFDP1 and decreased overall survival in patients with breast cancer.
Abba, M. C., Fabris, V. T., Hu, Y., Kittrell, F. S., Cai, W.-W., Donehower, L. A., Sahin, A., Medina, D., Aldaz, C. M. Identification of novel amplification gene targets in mouse and human breast cancer at a syntenic cluster mapping to mouse ch8A1 and human ch13q34. Cancer Res. 67: 4104-4112, 2007. [PubMed: 17483321] [Full Text: https://doi.org/10.1158/0008-5472.CAN-06-4672]
Bandara, L. R., La Thangue, N. B. Adenovirus E1a prevents the retinoblastoma gene product from complexing with a cellular transcription factor. Nature 351: 494-497, 1991. [PubMed: 1710781] [Full Text: https://doi.org/10.1038/351494a0]
Chen, C.-R., Kang, Y., Siegel, P. M., Massague, J. E2F4/5 and p107 as Smad cofactors linking the TGF-beta receptor to c-myc repression. Cell 110: 19-32, 2002. [PubMed: 12150994] [Full Text: https://doi.org/10.1016/s0092-8674(02)00801-2]
Gehrke, S., Imai, Y., Sokol, N., Lu, B. Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466: 637-641, 2010. [PubMed: 20671708] [Full Text: https://doi.org/10.1038/nature09191]
Girling, R., Partridge, J. F., Bandara, L. R., Burden, N., Totty, N. F., Hsuan, J. J., La Thangue, N. B. A new component of the transcription factor DRTF1/E2F. Nature 362: 83-87, 1993. Note: Erratum: Nature 365: 468 only, 1993. [PubMed: 8446173] [Full Text: https://doi.org/10.1038/362083a0]
Malas, S., Duthie, S. M., Mohri, F., Lovell-Badge, R., Episkopou, V. Cloning and mapping of the human SOX1: a highly conserved gene expressed in the developing brain. Mammalian Genome 8: 866-868, 1997. [PubMed: 9337405] [Full Text: https://doi.org/10.1007/s003359900597]
Zhang, Y., Venkatraj, V. S., Fischer, S. G., Warburton, D., Chellappan, S. P. Genomic cloning and chromosomal assignment of the E2F dimerization partner TFDP gene family. Genomics 39: 95-98, 1997. [PubMed: 9027491] [Full Text: https://doi.org/10.1006/geno.1996.4473]