Induction of Cell Cycle Arrest and B Cell Terminal Differentiation by CDK Inhibitor p18 and IL-6

Abstract

Cell cycle arrest and cell death are tightly coupled to terminal differentiation of B cells to plasma cells in vivo. This process was recapitulated in vitro by stimulation of IgG-bearing human B lymphoblastoid cells with interleukin-6 (IL-6), which led to orderly cell cycle arrest, differentiation, and apoptosis. In terminally differentiated plasmacytoid cells, phosphorylation of pRb was suppressed, correlating with the activation of the D-type cyclin-dependent kinase (CDK) inhibitors p18(INK4c) and p21(WAF1/CIP1). The expression of CDK6, however, remained unchanged. Activation of p18 by IL-6 was rapid, concomitant with marked enhancement of its association with CDK6 and cell cycle arrest. Overexpression of p18 in IgM-bearing lymphoblastoid cells, which differentiated in response to IL-6 but did not exit the cell cycle, reconstituted coupled differentiation and cell cycle arrest. Thus, CDK inhibitors, in particular p18, are likely to play a pivotal role in controlling cell cycle arrest and cell death in terminal differentiation of late-stage B cells to plasma cells via inhibition of pRb phosphorylation by CDK6.

Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1

“…Induction of di erentiation of B cells by IL-6 coincided with increased levels of p21 and p18 (Morse et al, 1997). During the di erentiation of mouse M1 cells an upregulation of p19 was observed (Narimatsu et al, 1997).…”

Comparison of the effectiveness of adenovirus vectors expressing cyclin kinase inhibitors p16INK4A, p18INK4C, p19INK4D, p21WAF1/CIP1 and p27KIP1 in inducing cell cycle arrest, apoptosis and inhibition of tumorigenicity

“…In vivo, apoptotic death often is observed in cells undergoing di erentiation processes as they exit the cell cycle (reviewed in Ho man and Lieberman, 1994;Liebermann et al, 1995) and CKI expression has been associated with di erentiation (Adachi et al, 1997;Morse et al, 1997;Steinman et al, 1994;Urashima et al, 1997). Potentially, overexpression of CKIs could induce aberrant differentiation processes with the cellular response to undergo apoptosis.…”

“…The p18 and p19 CKIs, as yet, have not been as well characterized. Cells of the myeloid lineage frequently express p18 and p19 (Schwaller et al, 1997), and p18 is thought to play a pivotal role in terminal di erentiation of late-stage B cells to plasma cells (Morse et al, 1997).…”

The INK4 family of cell cycle inhibitors in cancer

“…Second, induction of p19 INK4d occurs after IL-10 treatment of mouse macrophages, and this also leads to growth arrest (O'Farrell, Zindy, Roussel and Mui, unpublished). Third, p18 INK4c expression is rapidly activated by IL-6 in B cells programmed to di erentiate, and in myoblasts triggered to di erentiate to myotubes (Franklin and Xiong, 1996;Morse et al, 1997). Finally, p19 INK4d is highly expressed in terminally di erentiated neurons, and its expression is maintained in adulthood (Zindy et al, 1997b).…”