INHIBITION OF HMGI-C PROTEIN-SYNTHESIS SUPPRESSES RETROVIRALLY INDUCED NEOPLASTIC TRANSFORMATION OF RAT-THYROID CELLS

Elevated expression of the three high-mobility group I (HMGI) proteins (HMGI, HMGY, and HMGI-C) has previously been correlated with the pres ence of a highly malignant phenotype in epithelial and fibroblastic ra t thyroid cells and in experimental thyroid, lung, mammary, and skin c arcinomas. Northern (RNA) blot and run-on analyses demonstrated that t he induction of HMGI genes in transformed thyroid cells occurs at the transcriptional level. An antisense methodology to block HMGI-C protei n synthesis was then used to analyze the role of this protein in the p rocess of thyroid cell transformation. Transfection of an antisense co nstruct for the HMGI-C cDNA into normal thyroid cells, followed by inf ection with transforming myeloproliferative sarcoma virus or Kirsten m urine sarcoma virus, generated cell lines that expressed significant l evels of the retroviral transforming oncogenes v-mos or v-ras-Ki and r emoved the dependency on thyroid-stimulating hormones, However, in con trast with untransfected cells or cells transfected with the sense con struct, those containing the antisense construct did not demonstrate t he appearance of any malignant phenotypic markers (growth in soft agar and tumorigenicity in athymic mice). A great reduction of the HMGI-C protein levels and the absence of the HMGI(Y) proteins was observed in the HMGI-C antisense transfected, virally infected cells. Therefore, the HMGI-C protein seems to play a key role in the transformation of t hese thyroid cells.