Disease relevance of SPDEF

• Our results, as well as the critical roles of other Ets factors in cellular differentiation and tumorigenesis, strongly suggest that PDEF is an important regulator of prostate gland and/or prostate cancer development [1].
• High levels of prostate-derived Ets factor (PDEF) mRNA have been identified in breast cancer compared to normal breast [2].
• RT-PCR expression analysis of PDEF showed it to be overexpressed in 14 of 20 primary human breast tumors and in one metastases tested [3].
• These findings indicate that PDEF may be regulated by Erbb2 or EGFR-activated signaling pathways in breast cancer cells [4].

High impact information on SPDEF

• These regions contain not only functional but also sequence homology to the previously defined distal and proximal sequence elements (DSE and PSE) of the Xenopus U2 promoter, although U2 is transcribed by RNA polymerase II and U6 by RNA polymerase III [5].
• Using laser capture microdissection, we also found that PDEF mRNA is overexpressed in breast tumor epithelia throughout tumor progression [6].
• Novel role for PDEF in epithelial cell migration and invasion [6].

Biological context of SPDEF

• Cotransfection analyses demonstrated that NKX-3.1 can abolish the transcriptional activation function of PDEF on the prostate-specific antigen (PSA) promoter [7].
• PDEF, a novel prostate epithelium-specific ets transcription factor, interacts with the androgen receptor and activates prostate-specific antigen gene expression [1].
• Furthermore, cells coexpressing PDEF with either ErbB2 or CSF-1R/CSF-1 induced a dramatic invasive phenotype in three-dimensional cultures [6].
• By comparing to the baseline construct, PSE, containing the PSA enhancer (-5322 to -2855) fused to the proximal promoter (-541 to +12), the three most efficacious chimeric constructs, PSE-BA (insertion of ARE4), PSE-BC (duplication of core) and PSE-BAC (insertion of core and ARE4), are 7.3-, 18.9-, and 9.4-fold higher, respectively [8].
• Here we report a 2.0 A crystal structure of the PDEF Ets domain in complex with a natural, high-affinity DNA binding site in the promoter/enhancer region of the human prostate specific antigen gene [9].

Anatomical context of SPDEF

• Coimmunoprecipitation analyses demonstrated that NKX-3.1 and PDEF are physically associated in prostate epithelial cells [7].
• We also determined that Pdef protein is reduced in human invasive breast cancer and is absent in invasive breast cancer cell lines [10].
• A receiver operator characteristic curve analysis indicated that Prostate Specific Ets was overexpressed in 18 out of 22 lymph nodes containing metastatic breast cancer (82%) [11].
• Factors that interact with the U2E PSE, detected by a gel mobility shift assay and DNaseI footprinting, were present in blastula but not late gastrula embryos [12].

Associations of SPDEF with chemical compounds

• PDEF acts as an androgen-independent transcriptional activator of the PSA promoter [1].
• The combination of the serine residue at position 308 and the glutamine at position 311 explains the previous observation that the PDEF binds preferentially to a thymine at the +4 position of its binding site [9].
• The down-regulation of basal as well as DHT stimulated PDEF and PSA by silibinin demonstrates the antiproliferative potential of this agent [13].
• In this study we demonstrate the cancer protective potential of silibinin, a flavolignan derived from the fruits of Silybum marianum, which down-regulates the co-activator of the androgen receptor, the prostate epithelium-derived Ets transcription factor (PDEF) and consequently the secretion of PSA [13].
• The interaction of NKX-3.1 with full-length PDEF requires part of the homeodomain and a tyrosine-rich 21 amino acid sequence that lies C-terminal to the homeodomain [14].

Regulatory relationships of SPDEF

• Here we show that PDEF stimulates the p62 promoter through at least two sites, and likely acts as a coactivator [2].
• Furthermore, PDEF promoted anchorage-independent growth of ErbB2 and CSF-1R/CSF-1-expressing cells [6].

Other interactions of SPDEF

• Prostate-derived Ets factor (PDEF) was identified as a potential partner of NKX-3 [7].
• p62 overexpression in breast tumors and regulation by prostate-derived Ets factor in breast cancer cells [2].

Analytical, diagnostic and therapeutic context of SPDEF

• A sequence analysis indicated that mPse contains a conserved carboxy-terminal ETS DNA-binding domain and central Pointed domain, and the overall amino acid sequence shares 86% identity with that of hPSE [15].
• We used real-time RT-PCR to quantify mRNA expression of PDEF and PSA with gene-specific dual-labelled fluorescence probes [13].
• Immunohistochemistry and in situ hybridization analysis revealed that hPSE protein was translated in normal prostate glandular epithelial cells, but not in carcinoma cells with hPSE transcripts [16].

References