Disease relevance of TFE3

• Like the other muE3-binding proteins detected in nuclear extracts, in vitro-synthesized TFE3 also binds to the USF/MLTF site found in the adenovirus major late promoter [1].
• Translocations of TFE3 occur in specific subsets of human renal cell carcinomas and in alveolar soft part sarcomas [2].
• A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23) [3].
• We then applied this assay to a set of 11 pediatric renal carcinomas for which only paraffin-embedded tissue was available, to assess if morphologic features could predict TFE3 immunoreactivity [4].
• Thirty-nine of 40 neoplasms characterized by TFE3 gene fusions (19 of 19 alveolar soft part sarcoma, 20 of 21 renal carcinomas) demonstrated moderate or strong nuclear TFE3 immunoreactivity [4].

High impact information on TFE3

• Most cloned cells of MITF transfectants exhibited dendritic morphology and expressed melanogenic markers, but such properties were not observed in cells transfected with closely related TFE3 cDNA [5].
• In contrast, the BRG1-BAF155 complex does not interact or function with two unrelated transcription factors, TFE3 and NF-kappaB [6].
• Binding of both TFE3 and the Smad proteins to their cognate sequences is indispensable for TGF-beta-inducible activation of the PE2 promoter [7].
• Hence, TFE3 is an important transcription factor in at least one TGF-beta-activated signal transduction pathway [7].
• Binding by TFEB and TFE3 to related, but different, naturally occurring DNA target sequences was observed with distinct binding preferences [8].

Biological context of TFE3

• TFE3: a helix-loop-helix protein that activates transcription through the immunoglobulin enhancer muE3 motif [1].
• Using GAL4 fusion proteins, we mapped a strong transcription activation domain within TFE3 that is distinct from the leucine zipper and helix-loop-helix motifs and includes a potential negative amphipathic helix [1].
• The translocation results in a fusion of the transcription factor TFE3 gene on the X chromosome to a novel gene, designated PRCC, on chromosome 1 [9].
• Previously, we demonstrated that in t(X;1)(p11;q21)-positive renal cell carcinomas (RCCs), the TFE3 gene on the X chromosome is disrupted and fused to the PRCC gene on chromosome 1 [10].
• The basic helix-loop-helix leucine zipper (bHLHZIP) protein TFE3 and Smad3 synergistically activate transcription of the plasminogen activator inhibitor-1 (PAI-1) as well as other genes [11].

Anatomical context of TFE3

• Mitf also has been found-and TFE3 has been suggested-to modulate age-dependent changes in osteoclast function [12].
• In addition, the expression of PSF-TFE3 in normal renal proximal tubular epithelial cells from where such tumors originate leads to dedifferentiation and loss of some key functional proteins, which may reflect an initial step in the multistep process of tumor development [13].
• We have localized human TFE3 to the proximal short arm of the X chromosome using a somatic cell hybrid panel [14].
• We report a case of incidentally discovered ASPS in the uterine cervix of a 39-year-old woman that exhibited immunoreactivity for TFE3, a recently described marker of ASPS [15].
• Overexpression of TFE3 or TFEB in 3T3 cells activated endogenous and reporter E-cadherin expression [16].

Associations of TFE3 with chemical compounds

• The translocation is predicted to result in the fusion of the N-terminal region of the PRCC protein, which includes a proline-rich domain, to the entire TFE3 protein [17].

Physical interactions of TFE3

• TFE3 exhibited cooperative DNA binding with Smad proteins, whereas no cooperativity was observed between E47 and Smads [11].

Enzymatic interactions of TFE3

• TFECL contains an acidic domain that corresponds to a transcriptional activation domain of TFE3 but its equivalent region is deleted in rat TFEC [18].

Regulatory relationships of TFE3

• TFE3 can only stimulate enhancer activity in the presence of ITF-1 or in the absence of a microE5 motif [19].

Other interactions of TFE3

• Fusion of the transcription factor TFE3 gene to a novel gene, PRCC, in t(X;1)(p11;q21)-positive papillary renal cell carcinomas [9].
• Thus, TFE3-Smad3 response elements may represent a common target for TGF-beta-induced gene expression [20].
• Translocation RCC, bearing TFE3 or TFEB gene fusions, are recently recognized entities for which risk factors have not been identified [21].
• Synergism between transcription factors TFE3 and Smad3 in transforming growth factor-beta-induced transcription of the Smad7 gene [20].
• We demonstrate that the cytogenetically defined translocation t(X;1)(p11.2;p34) observed in papillary renal cell carcinomas results in the fusion of the splicing factor gene PSF located at 1p34 to the TFE3 helix-loop-helix transcription factor gene at Xp11 [22].

Analytical, diagnostic and therapeutic context of TFE3

• Carcinomas associated with TFE3 gene fusions may account for a significant proportion of pediatric renal carcinomas, and this immunohistochemistry assay may help to clarify their true prevalence [4].
• A relationship between these renal tumors and ASPS was initially suggested by the cytogenetic finding of a balanced t(X;17)(p11.2;q25) in two of the cases, and the ASPL-TFE3 fusion transcripts were then confirmed by reverse transcriptase-polymerase chain reaction [23].
• Southern blotting using a TFE3 genomic probe identified non-germline bands in several ASPS cases, consistent with rearrangement and possible fusion of TFE3 with a gene on 17q25 [24].
• By designing PCR primers, we were able to amplify various segments of the TFE3 genomic region, thus establishing that this gene is composed of seven exons, the first six of which are small (from 56 to 159 nt) [25].
• The differential diagnosis includes conventional-type papillary renal cell carcinoma, conventional-type (clear cell) renal carcinoma, and the ASPL-TFE3 renal carcinomas associated with the t(X;17)(p11.2;q25), with the latter two being morphologically the most similar to the t(X;1) renal carcinomas [26].

References