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Cyclin E2, a Novel Human G1 Cyclin and Activating Partner of CDK2 and CDK3, Is Induced by Viral Oncoproteins

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Cyclin E2, a Novel Human G1 Cyclin and Activating Partner of CDK2 and CDK3, Is Induced by Viral Oncoproteins Oncogene (1998) 17, 2787 ± 2798 ã 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 http://www.stockton-press.co.uk/onc Cyclin E2, a novel human G1 cyclin and activating partner of CDK2 and CDK3, is induced by viral oncoproteins Maimoona Zariwala1, Jidong Liu2 and Yue Xiong*,1,2,3 1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3280; 2Department of Biochemistry and Biophysics; University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599- 3280; 3Program in Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3280, USA G1 cyclin E controls the initiation of DNA synthesis by complexes with CDK4 or CDK6 to prevent the CDKs activating CDK2, and abnormally high levels of cyclin E from binding with and becoming activated by D-type expression have frequently been observed in human cyclins. The main function of CDK inhibitors is cancers. We have isolated a novel human cyclin, cyclin believed to couple diversi®ed growth inhibitory signals E2, that contains signi®cant homology to cyclin E. to the cell cycle clock. Cyclin E2 speci®cally interacts with CDK inhibitors of The decision to enter the replicative DNA synthesis the CIP/KIP family and activates both CDK2 and (S) phase or arrest in G1 is linked to diverse cellular CDK3. The expression of cyclin E2 mRNA oscillates processes such as signal transduction, cell differentia- periodically throughout the cell cycle, peaking at the tion, senescence, and oncogenic transformation G1/S transition, and exhibits a pattern of tissue (Hunter and Pines, 1994). In the budding yeast speci®city distinct from that of cyclin E1. Cyclin E2 Saccharomyces cerevisiae, the G1 cyclins Cln1 and encodes a short lived protein whose turnover is most Cln2 play the key role in determining the rate and fate likely governed by the proteasome pathway and is of G1 phase progression. Accumulation of CLN1 and regulated by phosphorylation on a conserved Thr-392 CLN2 proteins in G1 results in activation of Cdc28 residue. Expression of the viral E6 oncoprotein in normal kinase activity, thereby driving cells to passage through human ®broblasts increases the steady state level of a G1 restriction point known as START and to cyclin E2, but not cyclin E1, while expression of the E7 committing cells to initiate DNA synthesis (Reed, oncoprotein upregulates both. These data suggest that 1992). In mammalian cells, two CDK enzymes, CDK4 the expression of these two G1 E-type cyclins may be or CDK6 in combination with three D-type cyclins similarly regulated by the pRb function, but distinctly by (D1, D2 and D3) and CDK2 in association with cyclin the p53 activity. E, play the principle roles in regulating G1 progression (reviewed in Sherr, 1993, 1994). Although overexpres- Keywords: cyclin E2; CDK; G1 cell cycle control; cell sion of both D- and E-type cyclins similarly shorten transformation the G1 interval and reduce mitogen dependency (Ohtsubo and Roberts, 1993; Ohtsubo et al., 1995; Resnitzky et al., 1994), the function of these two cyclins are distinctly dierent in regulating G1 Introduction progression. While the function of cyclin D-associated kinase is largely dependent on the wild type pRB Progression through eukaryotic cell division cycle is (Guan et al., 1994; Lukas et al., 1995a, b; Koh et al., controlled by a family of protein serine/threonine 1995; Serrano et al., 1995; Medema et al., 1996), the kinases known as cyclin-dependent kinases (CDKs) function of cyclin E remains essential in Rb-negative which consist of an activating subunit, a cyclin, and a cells. The expression of cyclin D genes and the pRb catalytic subunit, a CDK. Sequential activation and kinase activity of the cyclin D-CDK4/6 enzymes are inactivation of CDK enzymatic function constitutes the induced during the delayed early response to mitogenic molecular basis for orderly progression through the cell stimulation, prior to the accumulation and kinase cycle. The primary positive and negative regulation of activity of cyclin E (Matsushime et al., 1991, 1994; CDK activity is mediated by the binding of a cyclin Meyerson and Harlow, 1994). The level of D cyclins and of a CDK inhibitor, respectively (Hunter and ¯uctuate little during the rest of the cell cycle. On the Pines, 1994). In mammals, two families of seven CDK other hand, the expression of cyclin E, but not CDK2, inhibitors have been identi®ed that dier in both is periodic during the cell cycle, peaking during G1 and structure and mechanism of action. Members of the declining during S phase (Lew et al., 1991; Dulic et al., CIP/KIP family contains three genes, p21CIP1/WAF1, 1992; Ko et al., 1992) and is necessary for S phase p27KIP1 and p57KIP2, that inhibit CDK activity by entry (Sherr, 1993; Duronio et al., 1996; Ohtsubo and forming a ternary p21-cyclin D-CDK4 complex. The Roberts, 1993; Ohtsubo et al., 1995; Pagano et al., INK4 family inhibitors which include four closely 1992; Resnitzky et al., 1994). These features suggest related ankyrin repeat containing genes, p16INK4a, that CDK4/6-cyclin D and CDK2-cyclin E enzymes p15INK4b, p18INK4c and p19INK4d, selectively form binary have distinct functions in regulating G1 progression, with cyclin D coupling extracellular growth signals to the cell cycle machinery while cyclin E controlling the initiation of DNA replication. *Correspondence: Y Xiong; E-mail: [email protected] Received date 11 September 1998; revised 22 October 1998; accepted The regulation of periodic accumulation and 22 October 1998 diminish of cyclin E is achieved largely through Novel human G1 cyclin E2 M Zariwala et al 2788 transcriptional activation of E2F during G1 (Duronio proteins, cyclin H has not been previously reported to and O'Farrell, 1995; Ohtani et al., 1995; Degregori et interact with CDK2. Whether in vivo CDK2 associates al., 1995; Botz et al., 1996; Geng et al., 1996), and with cyclin H and whether cyclin H can activate CDK2 subsequent degradation of cyclin E by the ubiquitin- kinase activity remains to be determined. In addition, a mediated proteolysis during S phase (Clurman et al., novel protein, encoded by clone HT376, was identi®ed 1996; Won and Reed, 1996). Deregulated cyclin E and con®rmed to strongly interact with CDK2K33M after expression could contribute to and may even be re-transformation of the rescued plasmid into yeast necessary for entering into S phase in cells which cells with CDK2K33M as bait (Figure 1a). This clone, would otherwise arrest in G1. Indeed, altered which codes for a novel human cyclin most closely expression of cyclin E has been frequently observed related to cyclin E (termed as cyclin E2), was chosen in human cancers. While genetic alteration of cyclin E for further study. gene rarely occurred in human cancer, abnormally high Cyclin E2 was cloned from the screen with mutant levels of cyclin E protein, resulted from either gene CDK2 suggesting that interaction between CDK2 and ampli®cation or deregulated degradation by the cyclin E2 may be facilitated by the mutation in CDK2. ubiquitin-mediated proteolysis pathway, have fre- To test this directly, cyclin E2 expressing HF7c yeast quently been observed in both primary tumors and cells were sequentially transformed with either mutant cancer-derived cell lines (reviewed in Hunter and Pines, or wild type CDK2. As shown in Figure 1, catalytic 1994; Sherr, 1996; Dou et al., 1996; Hall and Peters, inactive CDK2K33M, but not wild type CDK2, is 1996). Such frequent quantitative and qualitative capable of interacting with cyclin E2 as determined alteration of cyclin E expression and its correlation by growth on a selective media. These observations with increasing stage and grade of the tumor has led suggest that CDK2 and cyclin E2 may form a catalytic the proposal of using cyclin E as a potential prognostic active complex in yeast cells, causing either cyclin E2 marker for human cancer (Keyomarsi et al., 1997). degradation or interference with yeast CDC28 func- These observations suggest that although it is not a tion. Subsequent sequencing analysis revealed an in- proto-oncogene like cyclin D1, cyclin E overexpression frame stop codon between the GAL4 DNA binding might override certain growth inhibitory signals and domain and cyclin E2. This in-frame stop codon might thus contribute to cell transformation. In this report, reduce, but not completely terminate the synthesis of we describe a novel cyclin that shares signi®cant cyclin E2 so that there is sucient amount to interact sequence homology and many characteristic features with CDK2 bait. Removal of this stop codon with cyclin E, including activation of CDK2 and essentially arrested yeast cell growth (MZ, unpub- periodic oscillation during the cell cycle with a peaking lished observation). The basis for such intolerance of at the G1/S boundary. Expression of the papilloma cyclin E2 expression by yeast cells is not clear, but viral E6 oncoprotein in normal human ®broblasts could be caused by the ability of human cyclin E2 to increases the steady state level of cyclin E2, but not bind to and interfering the function of yeast CDC28. cyclin E1, suggesting distinct regulation mechanisms CDK3 is the closest relative to CDK2 among the for the two G1 E-type cyclins. nine mammalian CDK genes identi®ed thus far and its activating cyclin subunit has yet to be identi®ed. When tested in yeast cells, both the catalytically inactive CDK3K33M mutant and wild type CDK3 interact with Results cyclin E2 (Figure 1a), suggesting that cyclin E2 could potentially function as an activating cyclin subunit of Cloning of cyclin E2 CDK3 and that CDK3-cyclin E2 is functionally We used a catalytically inactive mutant of CDK2, distinct from the CDK2-cyclin E2 complex.
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