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P53 and P21 Form an Inducible Barrier That Protects Cells Against Cyclin E-Cdk2 Deregulation

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P53 and P21 Form an Inducible Barrier That Protects Cells Against Cyclin E-Cdk2 Deregulation View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Current Biology, Vol. 12, 1817–1827, October 29, 2002, 2002 Elsevier Science Ltd. All rights reserved. PII S0960-9822(02)01225-3 p53 and p21 Form an Inducible Barrier that Protects Cells against Cyclin E-cdk2 Deregulation Alex C. Minella,1,2 Jherek Swanger,1 Eileen Bryant,1 E-cdk2 is rate limiting and is required for G1 progression, Markus Welcker,1 Harry Hwang,1 and cyclin E abundance oscillates during the cell cycle and Bruce E. Clurman1,2,3 [2–5]. A pulse of cyclin E transcription in late G1 is regu- 1Divisions of Clinical Research and Human Biology lated by E2F activity, and this in part determines cyclin Fred Hutchinson Cancer Research Center E periodicity [6]. Cyclin E is an unstable protein, and 2 Department of Medicine ubiquitin-mediated proteolysis also determines its University of Washington School of Medicine abundance. Cyclin E turnover is regulated by site-spe- Seattle, Washington 98109 cific cyclin E phosphorylations, by binding to cdk2, and by the Fbw7/SCF ubiquitin ligase [7–10]. The Retinoblastoma protein (Rb) is phosphorylated Summary by cyclin D- and cyclin E-associated cdks during G1 progression. Progressive phosphorylation inactivates Background: Cyclin E, in conjunction with its catalytic Rb, and this promotes S phase entry. Most cancer cells partner cdk2, is rate limiting for entry into the S phase of contain mutations in the Rb-cyclin D pathway, although the cell cycle. Cancer cells frequently contain mutations the precise mechanisms through which these mutations within the cyclin D-Retinoblastoma protein pathway that promote tumorigenesis are largely unknown [11]. These lead to inappropriate cyclin E-cdk2 activation. Although mutations include gain-of-function mutations of cyclin deregulated cyclin E-cdk2 activity is believed to directly D and cyclin E and the loss of function of two classes contribute to the neoplastic progression of these can- of cdk inhibitor proteins that inhibit Rb phosphorylation cers, the mechanism of cyclin E-induced neoplasia is (the Cip/Kip and INK4 families), as well as Rb itself. unknown. Virtually all of these mutations may lead to inappropriate Results: We studied the consequences of deregulated cyclin E-cdk2 activity, which may then contribute di- cyclin E expression in primary cells and found that cyclin rectly to cell transformation. E initiated a p53-dependent response that prevented In established cell lines, ectopic cyclin E expression excess cdk2 activity by inducing expression of the causes faster progression through G1 phase, prolongs p21Cip1 cdk inhibitor. The increased p53 activity was the duration of S phase, and leads to decreased mitogen not associated with increased expression of the p14ARF requirements, altered cell size, and increased cell satu- tumor suppressor. Instead, cyclin E led to increased p53 ration density [4, 5, 12, 13]. Ectopic cyclin E expression serine15 phosphorylation that was sensitive to inhibitors in established cell lines has also been associated with of the ATM/ATR family. When either p53 or p21cip1 genetic instability and abnormal centrosome duplication was rendered nonfunctional, then the excess cyclin E [13, 14]. These activities have been suggested to under- became catalytically active and caused defects in S lie the association between cyclin E deregulation and phase progression, increased ploidy, and genetic insta- the development of cancer. bility. Deregulated cyclin E expression has also been linked Conclusions: We conclude that p53 and p21 form an to tumorigenesis in vivo. Cyclin E abnormalities have inducible barrier that protects cells against the deleteri- been described in many human cancers, and cyclin E ous consequences of cyclin E-cdk2 deregulation. A re- status has been correlated with poor clinical and/or his- sponse that restrains cyclin E deregulation is likely to tologic indices [15–18]. Mice with transgenes directing be a general protective mechanism against neoplastic cyclin E expression in the mammary epithelium develop transformation. Loss of this response may thus be re- breast carcinomas [19]. However, these tumors devel- quired before deregulated cyclin E can become fully oped in only 12% of animals with cyclin E transgenes oncogenic in cancer cells. Furthermore, the combination and after a long latent period. Similarly, transgenic mice of excess cyclin E and p53 loss may be particularly with cyclin E expression directed to the thymus did not genotoxic, because cells cannot appropriately respond spontaneously develop lymphomas, but they exhibited to the cell cycle anomalies caused by excess cyclin increased lymphomagenesis induced by carcinogens E-cdk2 activity. [20]. Thus, cyclin E deregulation was not sufficient for the development of these cancers, but it may have directly contributed to the multistep process of tumorigenesis. Introduction In order to further characterize the consequences of cyclin E deregulation in normal cells, we enforced cyclin Cell cycle transitions are catalyzed by the cyclin-depen- E expression in primary human and murine fibroblasts. dent kinases (cdks). Cdks are composed of a catalytic Unexpectedly, we found that prolonged expression of subunit (the cdk) and a regulatory subunit (a cyclin), and cyclin E in primary fibroblasts led to decreased cdk2 cyclin binding activates the cdk [1]. Progression through activity and inhibited, rather than promoted, cell cycle the G1 phase of the mammalian cell cycle is driven by progression. The decreased cdk2 activity was associ- the D-type cyclins, which activate the cdk4 and cdk6 ated with increased p21cip1 expression, and this re- kinases, and cyclin E, which activates cdk2. Cyclin quired intact p53 function. Furthermore, both p53 and p21 were required to suppress ectopic cyclin E in mouse 3 Correspondence: [email protected] embryo fibroblasts (MEFs). The activation of p53 by Current Biology 1818 (Figure 1). The increased p21 abundance was due to increased p21 mRNA, and not altered p21 turnover (Fig- ures S1B and S1C). In contrast, there was no increased abundance of the related p27Kip1 cdk inhibitor (not shown). Thus, deregulated cyclin E expression in pri- mary human fibroblasts led to increased p21cip1 abun- dance and cdk2 inactivation. Because p21 is a key transcriptional target of p53, we next examined if the increased p21 abundance resulted from increased p53 activity. Figure 2A shows that cyclin E overexpression in primary human foreskin fibroblasts (HFFs) caused increased p53 protein abundance that paralleled p21 abundance. To determine if increased p53 activity was required for the p21 induction, we first transduced cells with a vector encoding the human pap- illoma virus E6 protein (HPV-E6), which abrogates p53 function by catalyzing p53 degradation [21]. Thus, HPV- E6-expressing cells are effectively p53 null, although E6 may have activities in addition to p53 turnover. We found that expression of HPV-E6 completely inhibited the in- duction of p21 by cyclin E in WS1 human diploid fibro- blasts, HFFs, and WI-38 cells (Figures 2B and 2C and not shown). Furthermore, HPV-E6 expression reversed the inhibition of total cdk2 and cyclin A-cdk2 activity Figure 1. Deregulated Cyclin E Expression in Primary Human Fibro- blasts Leads to cdk2 Inhibition and Increased p21cip Expression caused by cyclin E and allowed the cyclin E to form WI-38 cells were transduced with retroviral vectors expressing active kinase complexes in all three primary fibroblast cyclin E, a hyperactive cyclin E mutant, cyclin E (T380A), or control isolates (Figure 2C and not shown). The loss of p21 vector. Cells were harvested 2 weeks after transduction and selec- expression did not significantly alter the amount of cdk2 tion. Western analysis of cyclin E and p21 abundance, and total that coprecipitated with cyclin E, but it instead resulted cdk2 activity measured in an anti-cdk2 immunoprecipitate kinase in a larger proportion of active cyclin E-cdk2 complexes assay, are shown. (Figure 2D). These data are consistent with the idea that the induction of p21 was due to increased p53 activity. The suppression of cdk2 activity resulting from cyclin cyclin E was associated with increased p53 serine 15 E expression was also p53 dependent, because, in the phosphorylation that was inhibited by caffeine or wort- absence of p53, this response no longer occurred. mannin, suggesting that it resulted from the ATM/ATR family of kinases. Moreover, when p53 function was Both p21 and p53 Are Required disabled, excess cyclin E-cdk2 activity caused aberrant for the Suppression of Ectopic Cyclin cell cycle regulation and genetic instability. These data E in Primary Mouse Fibroblasts indicate that excess cyclin E in primary cells initiates a Because HPV-E6 may have pleiotropic effects in addi- homeostatic p53-dependent program that limits cdk2 tion to p53 degradation, we also used MEFs with tar- activity via induction of p21. This response protects geted deletions in either p21 or p53 to directly test the normal cells from inappropriate cyclin E-cdk2 activity. role of these proteins in suppressing deregulated cyclin E activity [22, 23]. We found that, whereas ectopic cyclin Results E had minimal kinase activity in normal MEFs, the exoge- nous cyclin E was fully active in cells lacking either p21 Deregulated Cyclin E Expression in Primary or p53 (Figures 3A and 3B). Similarly, cyclin E overex- Human Fibroblasts Causes the Induction pression caused profound cell cycle anomalies in p21 of p53 and p21 null and p53 null MEFs compared with normal cells (Fig- We constructed retroviral vectors encoding either cyclin ures 3A and 3B). Enforced cyclin E expression only E or cyclin E (T380A), a mutant that is hyperactive be- minimally altered the cell cycle profile of asynchronous cause it is resistant to ubiquitin-mediated proteolysis normal MEFs (Figure 3A). Like other workers, we consis- [7, 10]. Transduction of WI-38 primary human diploid tently detected a small fraction of 8N cells in normal fibroblasts with either cyclin E or cyclin E (T380A) vectors MEFs [24].
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