Alternative splicing of the imprinted candidate tumor suppressor gene ZAC regulates its antiproliferative and DNA binding activities

ZAC encodes a zinc finger protein with antiproliferative activity, is mater nally imprinted and is a candidate for the tumor suppressor gene on 6q24, Z AC expression is frequently lost in breast and ovary tumor-derived cell lin es and down-regulated in breast primary tumors. In this report, we describe ZAC Delta2, an alternatively spliced variant of ZAC lacking the sequence e ncoding the two IV-terminal zinc fingers. Messenger RNAs encoding ZAC or ZA C Delta2 mere equally abundant and both proteins were nuclear. ZAC Delta2 d isplayed an improved transactivation activity and an enhanced affinity for a ZAC binding site, suggesting that the two N-terminal zinc fingers negativ ely regulated ZAC binding to its target DNA sequences. Both proteins were e qually efficient in preventing colony formation, indicating similar overall antiproliferative activities. However, these activities resulted from a di fferential regulation of apoptosis vs cell cycle progression since ZAC Delt a2 was more efficient at induction of cell cycle arrest than ZAC, whereas i t was the reverse for apoptosis induction. Hence, these data further underl ine that ZAC gene is critically controlled, both at the transcriptional lev el through imprinting and at the functional level through alternative splic ing.