Disease relevance of TFEB

• Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution [1].
• Alpha-TFEB is thus identified as a fusion gene in a subset of pediatric renal neoplasms [2].
• TFEB was isolated by virtue of its binding to the major late promoter of adenovirus [3].
• Renal carcinomas with the t(6;11)(p21;q12): clinicopathologic features and demonstration of the specific alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR [4].

High impact information on TFEB

• Binding by TFEB and TFE3 to related, but different, naturally occurring DNA target sequences was observed with distinct binding preferences [3].
• TFEB has DNA-binding and oligomerization properties of a unique helix-loop-helix/leucine-zipper family [3].
• In two primary tumors we found that Alpha, an intronless gene, rearranges with the first intron of TFEB, just upstream of TFEB's initiation ATG, preserving the entire TFEB coding sequence [2].
• Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation [2].
• We describe the rational design of a DNA-binding antibody, Fab-Ebox, by replacing a variable segment of the immunoglobulin heavy chain with a 17-amino acid domain derived from TFEB, a class B basic helix-loop-helix protein [5].

Chemical compound and disease context of TFEB

• A highly distinctive subset of renal neoplasms of children and young adults contains a t(6;11)(p21;q12), a translocation recently been shown to result in fusion of Alpha, a gene on 11q12, with the transcription factor gene TFEB on 6p21 [4].
• Using a polyclonal antibody to TFEB on formalin-fixed, paraffin-embedded tissue sections, we found that all 7 renal neoplasms with the t(6;11) demonstrated moderate (2 cases) or strong (5 cases) nuclear TFEB immunoreactivity [4].

Biological context of TFEB

• Additional transfection studies revealed that the TFEB protein encoded by the AlphaTFEB fusion gene is efficiently targeted to the nucleus [1].
• Here we show that in t(6;11)(p21;q13)-positive RCCs the TFEB gene on chromosome 6 is fused to the Alpha gene on chromosome 11 [1].
• Seven alternative 5' exons were identified in the TFEB gene, of which three displayed specific expression in placenta and brain, respectively [6].
• The protein encoded by this cDNA, TFEB, probably recognizes E-box sequences in the heavy-chain immunoglobulin enhancer [7].
• MITF and its related family members TFE3 and TFEB heterodimerize with each other, recognize the same DNA sequences, and are subject to many of the same post-translational modifications [8].

Anatomical context of TFEB

• Nuclear immunoreactivity for TFEB in normal tissues was extremely rare, limited to weak labeling of scattered benign lymphocytes [4].
• In mouse embryonic fibroblasts, TFE3 and TFEB activation of E-cadherin was responsive to leukemia inhibitory factor [9].
• Overexpression of TFE3 or TFEB in 3T3 cells activated endogenous and reporter E-cadherin expression [9].

Associations of TFEB with chemical compounds

• Fluorescence in situ hybridization confirmed the involvement of both TFEB and Alpha in this translocation [2].
• Based on these results we conclude that the RCC-associated t(6;11)(p21;q13) translocation leads to a dramatic transcriptional and translational upregulation of TFEB due to promoter substitution, thereby severely unbalancing the nuclear ratios of the MITF/TFE subfamily members [1].
• Comparable interference of binding by methylation of cytosine residues indicated that Fab-Ebox and TFEB both contact DNA through interactions along the major groove of double-stranded DNA [5].
• The dimerization stability of the HLH-LZ transcription protein family is modulated by the leucine zippers: a CD and NMR study of TFEB and c-Myc [10].
• Comparison of the Delta V values for these ethers with those of the previously studied(37-39) monolayers of trifluoroethyl ester (TFEB) and ethyl ester of behenic acid (EB) shows that the reversal of the sign of Delta V causes the same change Delta(Delta V) = -706 +/- 16 mV due to fluorination of heads [11].

Other interactions of TFEB

• Translocation RCC, bearing TFE3 or TFEB gene fusions, are recently recognized entities for which risk factors have not been identified [12].
• We found that, similar to the MiTF gene, the genes for TFEB and TFEC contain multiple alternative first exons with restricted and differential tissue distributions [6].
• The DNA-binding factor TFEB contains adjacent helix-loop-helix (HLH) and leucine zipper (LZ) domains flanked by an upstream basic region [3].
• The TFEB protein is known to form homodimers. c-Myc, on the other hand, does not homodimerize in vivo, but is mostly found in heterodimeric complexes with Max, another protein of the HLH-LZ family [10].

Analytical, diagnostic and therapeutic context of TFEB

• Quantitative PCR analysis revealed that AlphaTFEB mRNA levels are up to 60-fold upregulated in primary tumor cells as compared with wild-type TFEB mRNA levels in normal kidney samples, resulting in a dramatic upregulation of TFEB protein levels [1].
• Both types of translocation result in overexpression of the fusion gene products, such that nuclear labeling for TFE3 or TFEB by immunohistochemistry is a sensitive and specific marker of these respective tumor types [13].
• DNA-binding activity was studied by electrophoretic mobility-shift assays in which Fab-Ebox was shown to form a specific complex with DNA containing the TFEB recognition motif (CACGTG) [5].
• In this paper, we present a structural characterization of synthetic peptides encompassing the leucine zipper sequences of c-Myc and TFEB, using circular dichroism, analytical ultracentrifugation, and nuclear magnetic resonance [10].
• We also show that the Alpha-TFEB fusion RNAs are highly variable in size and structure, making detection by reverse-transcriptase polymerase chain reaction (RT-PCR) less reliable than for other gene fusions [4].

References