CHARACTERIZATION OF THE PROMOTER REGION AND OLIGOMERIZATION DOMAIN OFH4 (D10S170), A GENE FREQUENTLY REARRANGED WITH THE RET PROTOONCOGENE

PTC-1, the predominant form of PTC oncogene in human papillary thyroid carcinoma, encodes a fusion protein containing the N-terminus of H4 ( D10S170) fused 5' to the ret tyrosine kinase domain. Accordingly, the PTC-1 expression is driven by the H4 gene promoter. Our study showed t hat H4 is expressed in various human tissues, including thyroid. Furth ermore, we have localized the transcriptional start sites of H4 to a r egion 100 to 190 bp upstream of the translation initiation site (ATG) by primer extension assay, and the 114 promoter to a region within 259 bp upstream of the ATG site by luciferase assay. Interestingly, prote in sequence analysis indicated a potential coiled-coil domain in the N -terminal region of H4. Indeed, oligomerization was demonstrated by an in vitro assay with recombinant proteins containing this region. As d imerization is considered to be a crucial step for receptor tyrosine k inase activation, we hypothesize that both unscheduled expression of r et tyrosine kinase and constitutive oligomerization of PTC-1 proteins are responsible for PTC-1 transforming activity in thyroid.