TERMINALLY DIFFERENTIATED SKELETAL MYOTUBES ARE NOT CONFINED TO G(0) BUT CAN ENTER G(1) UPON GROWTH-FACTOR STIMULATION

Terminally differentiated cells are specialized cells unable to prolif erate that constitute most of the mammalian body. Despite their abunda nce, little information exists on the characteristics of cell cycle co ntrol in these cells and the molecular mechanisms that prevent their p roliferation, They are generally believed to be irreversibly restricte d to the G(0) state, In this report, we define some features of a para digmatic terminally differentiated system, the skeletal muscle, by stu dying its responses to various mitogenic stimuli, We show that forced expression of a number of cell cycle-regulatory genes, including erbB- 2, v-ras, v-myc, B-myb, Id-1, and E2F-1, alone or in combinations, can not induce terminally differentiated skeletal muscle cells (myotubes) to synthesize DNA, However, serum-stimulated myotubes display a typica l immediate-early response, including the up-regulation of c-fos, c-ju n, c-myc, and Id-1, They also elevate the expression of cyclin D1 afte r 4 hours of serum treatment, All these events take place in myotubes in a way that is indistinguishable from that of quiescent, undifferent iated myoblasts reactivated by serum, Moreover, pretreatment with seru m shortens the time required by E1A to induce DNA synthesis, confirmin g that myotubes can partially traverse G(1), Serum growth factors do n ot activate late-G(1) genes in myotubes, suggesting that the block tha t prevents terminally differentiated cells from proliferating acts in mid-G(1), Our results show that terminally differentiated cells are no t confined to G(0) but can partially reenter G(1) in response to growt h factors; they contribute to a much-needed definition of terminal dif ferentiation, The important differences in the control of the cell cyc le between terminally differentiated and senescent cells are discussed .