SARPS - A FAMILY OF SECRETED APOPTOSIS-RELATED PROTEINS

Quiescent mouse embryonic C3H/10T1/2 cells are more resistant to diffe rent proapoptotic stimuli than are these cells in the exponential phas e of growth, However the exponentially growing 10T1/2 cells are resist ant to inhibitors of RNA or protein synthesis, whereas quiescent cells die upon these treatments, Conditioned medium from quiescent 10T1/2 c ells possesses anti-apoptotic activity, suggesting the presence of pro tein(s) that function as an inhibitor of the apoptotic program. Using differential display technique, me identified and cloned a rDNA design ated sarp1 (secreted apoptosis-related protein) that is expressed in q uiescent bur not in exponentially growing 101/2 cells. Hybridization s tudies with sarp1 revealed two additiional family members, Cloning and sequencing of sarp2 and sarp3 revealed 38% and 40% sequence identity to sarp1, respectively. Human breast adenocarcinoma MCF7 cells stably transfected with sarp1 or infected with SARP1-expressing adenovirus be came more resistant, whereas cells transfected with sarp2 displayed in creased sensitivity to different proapoptotic stimuli. Expression of s arp family members is tissue specific, sarp mRNAs encode secreted prot eins that possess a cysteine-rich domain (CRD) homologous to the CRD o f frizzled proteins but lack putative membrane-spanning segments, Expr ession of SARPs modifies the intracellular levels of beta-catenin, sug gesting that SARPs interfere with the Wnt-frizzled proteins signaling pathway.