Growth retardation in mice lacking the proteasome activator PA28 gamma

The proteasome activator PA28 binds to both ends of the central catalytic m achine, known as the 20 S proteasome, in opposite orientations to form the enzymatically active proteasome. The PA28 family is composed of three membe rs designated alpha, beta, and gamma; PA28 alpha and PA28 beta form the het eropolymer mainly located in the cytoplasm, whereas PA28 gamma forms a homo polymer that predominantly occurs in the nucleus. Available evidence indica tes that the heteropolymer of PA28 alpha and PA28 beta is involved in the p rocessing of intracellular antigens, but the function of PA28 gamma remains elusive. To investigate the role of PA28 gamma in vivo, we generated mice deficient in the PA28 gamma gene. The PA28 gamma-deficient mice were born w ithout appreciable abnormalities in all tissues examined, but their growth after birth was retarded compared with that of PA28 gamma(+/-) or PA28 gamm a(+/+) mice. We also investigated the effects of the PA28 gamma deficiency using cultured embryonic fibroblasts; cells lacking PA28 gamma were larger and displayed a lower saturation density than their wild-type counterparts. Neither the expression of PA28 alpha/beta nor the subcellular localization of PA28 alpha was affected in PA28 gamma(-/-) cells. These results indicat e that PA28 gamma functions as a regulator of cell proliferation and body g rowth in mice and suggest that neither PA28 alpha: nor PA28 beta compensate s for the PA28 gamma deficiency.