Virus-encoded cyclin.

Abstract

The eukaryotic cell cycle is believed to be regulated at two decision points: the G1-to-S transition and the G2-to-M transition (14, 38). These transitions require protein kinase activity in association with regulatory proteins called cyclins. Cellular cyclins are found in association with cyclin-dependent kinases (cdks), and their activities and functions in regulating cell cycle progression are absolutely dependent on this interaction (14, 36). The most extensively characterized cyclin is the mitotic cyclin B. Cyclin B forms complexes with cdc2 to regulate both mitotic entry and exit (31, 33). Cyclin A can associate independently with cdc2 and with a related cyclin-dependent kinase, cdk2, during the S and G2 phases of the cell cycle (34). Novel G1 cyclins called C, D, and E have been identified and studied (7, 18, 20, 21, 23, 25-27, 30, 43). Cyclins D1, D2, and D3 were found to associate with the catalytic subunit of cdk4 (p34PSK-J3), which is distinct from other known cdks (26).Xiong et al. (44,45) showed that cyclins Dl and D3 were associated with three different cyclin-dependent kinases, cdk2, cdk4, and cdk5, along with proliferating cell nuclear antigen and a kinase inhibitory protein, p21. Direct binding of cyclin D to the Rb protein and in vitro Rb phosphorylation by the cyclin D-dependent kinase cdk4 have been reported (6,8,18,26). Recently, the PLSTIRE gene product was demonstrated to contain cell cycle-dependent kinase activity and renamed cdk6 (cyclin-dependent kinase 6) (2,29

Physical Interaction of Human T-Cell Leukemia Virus Type 1 Tax with Cyclin-Dependent Kinase 4 Stimulates the Phosphorylation of Retinoblastoma Protein

“…Additionally, some transforming herpesviruses even encode viral homologues of cellular D cyclins which form stable complexes with CDK4 and CDK6. In contrast to their cellular counterparts, these viral cyclins are completely resistant to inhibition by CKIs (25,50). Interestingly, the capacity of DNA tumor viruses to stimulate the G 1 -to S-phase progression is frequently complemented by a p53-inactivating function (22).…”

“…Many viral oncoproteins from herpesviruses (vCyc and kCyc), adenoviruses (E1A), and papovaviruses (simian virus 40 [SV40] large T antigen and human papillomavirus E7) affect G 1 -specific cyclin-dependent kinases (CDKs) and/or their cognate substrate, retinoblastoma (Rb) protein (pRb) (22,25,50). CDK4 and its close relative CDK6 bind to cyclin D isotypes and, together with CDK2 complexes, integrate mitogenic and growth-inhibitory signals.…”

CAK-independent Activation of CDK6 by a Viral Cyclin

“…Like the related v-cyclin from herpesvirus saimiri (Jung et al, 1994), the KSHV-cyclin can activate CDK6 (Jung et al, 1994;Chang et al, 1996;Godden-Kent et al, 1997;Li et al, 1997). CDK6/KSHV-cyclin complexes can phosphorylate the Retinoblastoma protein (Rb) and, unlike CDK6/cyclin D complexes, can also phosphorylate histone H1 (Jung et al, 1994;Godden-Kent et al, 1997;Li et al, 1997;Ellis et al, 1999;Mann et al, 1999), p27 (Ellis et al, 1999Mann et al, 1999), Id-2 (Mann et al, 1999), Orc1 (Laman et al, 2001), and CDC25A . CDK6/KSHV-cyclin complexes have been reported to be insensitive to inhibition by p16 (Swanton et al, 1997) and to be insensitive (Swanton et al, 1997) or less sensitive (Ellis et al, 1999) to inhibition by p27 in vitro.…”

ICP0 enables and monitors the function of D cyclins in herpes simplex virus 1 infected cells

“…This function involves the activation of cdk4 by cyclin D3. The results presented here raise two questions: First, what is the function of cyclin D3 and, second, why has HSV-1 evolved the recruitment of cyclin D3 rather than the acquisition or recruitment of cyclin D2, as have other herpes viruses (16)(17)(18)(19)?…”

“…Noteworthy here are that several members of the herpesvirus family encode orthologs of cyclin D2 and that although each D cyclin appears to have specific functions, the basic functions of the D cyclins with respect to initiation of S phase, cell growth, and differentiation appear to be interchangeable (15)(16)(17)(18)(19).…”