Cytokine response gene 6 induces p21 and regulates both cell growth and arrest

Cytokine response gene #6 (CR6), cloned from interleukin 2-stimulated T lym phocytes, is homologous to GADD45 and MyD118, genes which promote cell cycl e arrest and apoptosis, To determine how this gene family could possibly me diate both cell survival/proliferation and cell cycle arrest/death, transfe ctants were generated so that the genes could be expressed ectopically, ind ependently from their normal inducing agents. In cycling retinoblastoma pro tein-negative (pRb-) cells, ectopic CR6 expression blocked G2/M transition, but did not prevent G1/S transition so that endoreduplication resulted. By comparison, when CR6, GADD45, and MyD118 genes were expressed ectopically in proliferating pRb(+) cells, either G1/S or G2/M transition was effective ly blocked, so that there was no endoreduplication, Consistent with these f indings, in proliferating pRb-cells, ectopic expression of CR6 promoted the expression of both G1 and G2/M cyclins, By comparison, in pRb+ cells, the expression of G1 cyclins was increased, while expression of the mitotic cyc lins was decreased. However, in pRb(+) cells, cyclin-dependent kinase activ ities associated with both G1 and G2/M cyclins were decreased. Moreover, ec topic expression of all three genes resulted in the expression of the CKI, p21, both in pRb- and pRb(+) cells. The physiologic induction of CR6 expres sion by IL2 in quiescent normal human T cells occurs transiently in the fir st half of G1, coordinately with the expression of p21, Therefore, this gen e family regulates G1 and G2, and promotes either cell growth or arrest by a common mechanism.