Ubiquitin-independent degradation of cell-cycle inhibitors by the REGγ proteasome

The cell-cycle regulator p21(Cip1) is degraded by proteasomes independently of ubiquitination. We now show that degradation of p21 in vivo does not require the 19S proteasome lid, which contains the ubiquitin-binding subunit. Instead, the major proteasomal pathway for p21 degradation involves an alternative proteasome lid, the REG gamma complex. REG gamma binds to p21 in vivo, and deletion of p21's REG gamma-binding site greatly extends its half-life. Knockdown of REG gamma by RNA interference stabilizes p21, p21 has a significantly extended half-life in REG gamma(-/-) murine embryonic fibroblasts, and the p21 abundance is elevated in REG gamma(-/-) mice. The role of REG gamma in cell-cycle regulation may extend beyond p21 regulation, because p16(INK4A) and p19(Arf) also bind to REG gamma and are stabilized in REG gamma-deficient cells.