ONCOGENIC TRANSFORMATION AND INHIBITION OF ADIPOCYTIC CONVERSION OF PREADIPOCYTES BY TLS FUS-CHOP TYPE-II CHIMERIC PROTEIN/

Myxoid Liposarcomas are characterized by t(12; 16)(q13;p11) translocat ion and expression of TLS/ FUS-CHOP chimeric transcripts (types I to I II). Among these, the type II transcript is expressed in the majority of cases of myxoid and round cell liposarcoma. To investigate the func tion of the type II chimeric protein, we obtained stable transformants of ST-13, a murine preadipocytic cell line, which express TLS/FUS-CHO P type II protein (ST-TC) or CHOP protein (ST-C) as well as vector-tra nsfected controls (ST-V), ST-TC and ST-C cells showed almost complete or partial resistance to adipogenic conversion by insulin and thiazoli dinedione, respectively. Induction by adipogenic stimulation of the ad ipocytic genes such as C/EBP alpha, aP2, and adipsin was almost totall y suppressed in the ST-TC cells, whereas In ST-C cells C/EBP alpha alo ne was induced without induction of aP2 and adipsin, Transcriptional s uppression of the C/EBP alpha gene in ST-TC cells was suggested by the results of chloramphenicol acetyltransferase (CAT) assay showing a si gnificantly lower C/EBP alpha promoter activity compared with findings in ST-C and ST-V cells, Failure to rescue adipogenic conversion by ec topic expression of C/EBP alpha in ST-TC cells suggested a functional impairment of C/EBP alpha to induce expression of downstream genes, TL S/FUS-CHOP type II protein showed transforming activity, as evidenced by loss of contact inhibition of growth, anchorage-independent growth in soft agar, and tamer formation in nude mice, showing typical histol ogical features of myxoid liposarcoma seen in humans, These findings s uggest important roles for TLS/FUS-CHOP type II protein in the oncogen esis of myxoid liposarcoma.