A THYMUS-SPECIFIC MEMBER OF THE HMG PROTEIN FAMILY REGULATES THE HUMAN T-CELL RECEPTOR C-ALPHA-ENHANCER

The human T cell-specific transcription factor TCF-1-alpha plays a key role in the tissue-specific activation of the T cell receptor (TCR) C-alpha enhancer and binds to pyrimidine-rich elements (5'-PyCTTTG-3') present in a variety of other T cell-specific control regions. Using amino acid sequence information derived from the DNA affinity-purified protein, we have now isolated cDNA clones encoding TCF-1-alpha. The TCF-1-alpha cDNA contains a single 68-amino-acid domain that is homologous to a region conserved among high-mobility group (HMG) and nonhistone chromosomal proteins. Expression of full-length and mutant cDNA clones in bacteria reveal that the single HMG motif, which is predicted to contain two extended alpha-helical segments, is sufficient to direct the sequence-specific binding of TCF-1-alpha to DNA. Northern blot experiments demonstrate further that TCF-1-alpha mRNA is highly tissue specific, found primarily in the thymus or T cell lines. The immature CEM T cell line expresses relatively low levels of TCF-1-alpha mRNA, which are increased upon activation of these cells by phorbol esters. Interestingly, the cloned TCF-1-alpha protein is a potent transcriptional activator of the human TCR-alpha enhancer in nonlymphoid cell lines, whereas the activity of the endogenous protein in T cell lines is strongly dependent on an additional T cell-specific protein that interacts with the core enhancer. TCF-1-alpha is currently unique among the newly emerging family of DNA-binding regulatory proteins that share the HMG motif in that it is a highly tissue-specific RNA polymerase II transcription factor.