CYCLIN D3 - REQUIREMENT FOR G1 S TRANSITION AND HIGH ABUNDANCE IN QUIESCENT TISSUES SUGGEST A DUAL ROLE IN PROLIFERATION AND DIFFERENTIATION/

The mammalian D-type cyclins DI, D2, and D3 activate the cyclin-depend ent kinases CDK4 and CDK6 in G1 and thereby promote the cell's commitm ent to enter S phase. To elucidate the extent of functional overlap am ong the D-type cyclins, we have examined several aspects of the least characterized member of this subfamily of G1 cyclin proteins, cyclin D 3. Microinjection of cyclin D3-neutralizing antibody inhibited G1/S tr ansition in human (IMR-90) and rat (R12) diploid fibroblasts, indicati ng that analogous to cyclins D1 and D2, cyclin D3 is essential for tim ely progression through Gf. In contrast to cyclins D1 and D2, cyclin D 3 was (i) ubiquitously expressed among a panel of 70 human cultured ce ll types; (ii) strongly upregulated upon induction of HL-60 leukaemia cells to differentiate; and (iii) accumulated to high levels in a wide range of quiescent cell types in mouse and human differentiated tissu es. Complementary analyses of human biopsies and mouse tissues at diff erent stages of foetal and postnatal development revealed lineage-depe ndent transient or long-term accumulation of the cyclin D3 protein, co rrelating with initiation/establishment or maintenance of the mature p henotypes, respectively. Our data support the notion that the biologic al roles of the individual D-type cyclins are not fully redundant, and suggest a possible dual role for cyclin D3 in cell proliferation and induction and/or maintenance of terminal differentiation.