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Cell-Specific Responses to Loss of Cyclin-Dependent Kinases

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Cell-Specific Responses to Loss of Cyclin-Dependent Kinases Oncogene (2007) 26, 4469–4477 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Cell-specific responses to loss of cyclin-dependent kinases C Berthet and P Kaldis Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, USA Inactivation of cyclin-dependent kinases (Cdks) and/or one or more components of the cell cycle machinery cyclins in mice has changed our viewof cell cycle (reviewed by Pagano and Jackson (2004); Aleem and regulation. In general, cells are far more resistant to the Kaldis (2006); Santamaria and Ortega (2006)), and in loss of Cdks than originally anticipated, suggesting wide- this review, we will outline how the lack of Cdk/cyclin spread compensation among the Cdks. Early embryonic complexes can affect cells (and organism) that rely on cells are, so far, not sensitive to the lack of multiple Cdks their proliferation status. We will report new insights or cyclins. In contrast, differentiated cells are more that these mouse models provide to understand pro- dependent on Cdk/cyclin complexes and the functional liferation control in stem cells, differentiated cells and redundancy is more limited. Our challenge is to better transformed cells. To a certain degree, these mouse understand these cell-type specific differences in cell cycle models mimic drugs that target these cell cycle proteins regulation that can be used to design efficient cancer and interpretation of the observed mutant phenotypes therapy. Indeed, tumor cells seem to respond to inhibition can improve our strategies for cancer therapy. of Cdk activities, however, with different outcome depend- Cell proliferation is a tightly regulated process and ing on the tumor cell type. Tumor cells share some most eukaryotic cells undergo cell division only in the proliferation features with stem cells, but appear more presence of mitogenic factors. The cell cycle machinery sensitive to loss of Cdk activity, somewhat resembling includes several mechanisms to sense the presence of differentiated cells. We summarize the current knowledge these growth factors, inhibitory factors or damage that of cell cycle regulation in different cell types and highlight prevents cell cycle progression. Different checkpoints their sensitivity to the lack of Cdk activities. along the cell division cycle determine progression or Oncogene (2007) 26, 4469–4477; doi:10.1038/sj.onc.1210243; arrest and eventually may trigger cell death. At the onset published online 5 February 2007 of the cell cycle, mitogenic factors stimulate the expression of proto-oncogenes, such as Ras or Myc, Keywords: cyclin; cyclin-dependent kinase; cell cycle; which results in transcriptional regulation leading to embryonic stem cells; tumor cells; differentiated cells increased proliferation. The family of D-type cyclins is the first to be induced through these mitogenic path- ways, followed by the expression of cyclins E1 and E2. The D-type cyclins stimulate the activity of Cdk4/Cdk6, Introduction whereas E-type cyclins enhance Cdk2 activity. These complexes lead to passage through the restriction (R) Cell proliferation occurs at different rates depending on point at the boundary of the G1 and S phase, where extracellular factors and the genetic profile of cells, after the cell cycle progresses independently of growth which determines their pluripotency, differentiation factors. The key event in the G1 phase is the status and eventually their transformation grade. The phosphorylation of the pocket proteins (Retinoblastoma proliferation rate is regulated by proteins involved in the protein (Rb), p107, p130) by Cdk/cyclin D and E control of the cell cycle, which is driven by cyclins and complexes. Each Cdk complex phosphorylates presum- their associated kinases (Cdk for cyclin-dependent ably distinct residues of Rb (and the other pocket kinase) (Morgan, 1997). The fluctuating activities of proteins), and it has been postulated that this specificity several Cdk/cyclin complexes establish the progression provides a mechanism for temporal control of Rb of the cell cycle through each phase (G1, S, G2 and M). during G1 (reviewed by Mittnacht (1998); Knudsen and The composition and regulation of Cdks vary according Knudsen (2006)). Phosphorylation of Rb leads to the to cell type and environment. In the past few years, release of E2F proteins, resulting in the transcription of numerous mouse models have been generated targeting genes essential for entry into S phase. When mitogenic signals are not strong enough to enhance Cdk activity and inactivate Rb, cells cannot enter into S phase but Correspondence: Dr P Kaldis, Mouse Cancer Genetics Program, eventually will exit the cell cycle and acquire a reversible Center for Cancer Research, National Cancer Institute-Frederick, non-replicative state, quiescence or G0. The G1/S Bldg. 560/22-56, 1050 Boyles Street, Frederick, MD 21702-1201, USA. transition can also be affected by inhibitory signals E-mail: [email protected] Received 30 November 2006; accepted 30 November 2006; published (e.g., cell contact inhibition or by different stresses, such online 5 February 2007 as oxidative stress, DNA damage, etc) inducing the Cdk functions in different cell types C Berthet and P Kaldis 4470 expression of anti-proliferative signals. Tumor suppres- sor genes constitute these signaling pathways, which result in the inhibition of Cdk activity. The INK4 (p15Ink4b, p16Ink4a, p18Ink4c and p19Ink4d) and the CIP/KIP (p21Cip1,p27Kip1 and p57Kip2) families inhibit cyclin D and E complexes, respectively, and are among these tumor- suppressor genes (reviewed by Sherr and Roberts (1999)). Consistently, mice with defects in Cdk inhibi- tors (CKIs) are cancer prone (reviewed by Santamaria and Ortega (2006)). Moreover, expression of some of these CKIs is directly or indirectly regulated by p53, one of the major tumor-suppressor genes (reviewed by Vousden and Lu (2002)). The activation of p53 or Rb under stress conditions can irreversibly affect cells that will enter senescence, a permanent non-replicative state (reviewed by Campisi (2005)). Cell-cycle progression can also be blocked at other checkpoints (intra S phase, G2/M, mitosis) following cellular damage. These path- ways usually activate p53 and/or p21, which will then inhibit Cdk2 and/or Cdk1 activity. At all the check- points, cells remain arrested until damage is repaired or cells undergo apoptosis. If cell death is avoided and cell cycle arrest is bypassed, it might lead to cell transforma- tion. The balance between mitogenic, anti-mitogenic, apoptotic and stress response signals determines the fate of the cells and their ability to proliferate. Embryonic stem (ES) cells proliferate at a fast rate (cell cycle length of B8 h) and exhibit a short G1 phase (Figure 1a). Mouse ES cells are deficient in cyclin D-associated activity (Savatier et al., 1996; Burdon et al., 2002; Jirmanova et al., 2002) and rely on Cdk2 activity to drive the G1/S transition (Stead et al., 2002). Figure 1 Cell cycle regulators in different cell types. Stem cells (a), Components of the G1 checkpoint, such as Rb are differentiated cells (b) and tumor cells (c) regulate the cell cycle permanently inactivated (reviewed by Burdon et al. according to their specific environment. The G1-phase regulation is (2002)) and despite high levels of p53 expression in particularly modified in each cell type. The RB/E2F and p53 pathways are not active in stem cells and Cdk1 seems to be the mouse ES cells, cell cycle progression is not affected. major kinase regulating all the phases. During differentiation, the It appears that the p53-mediated response is inactive cells proliferate under the strict control of multiple Cdk/cyclin because p53 is sequestered into the cytoplasm (Aladjem complexes and their inhibitors. These inhibitory pathways are often et al., 1998; Prost et al., 1998). Indeed, ES cells do not inactivated in tumor cells, which lead to hyper-activation of the undergo G1/S cell-cycle arrest under stimuli that would Cdk/cyclin complexes. normally activate the p53-mediated pathway in somatic cells, whereas the cell-cycle arrest response is restored upon differentiation of ES cells (Aladjem et al., 1998; mouse resulting in reduced longevity and an early onset Prost et al., 1998). In contrast, the G2/M checkpoint of an aging phenotype (Tyner et al., 2002). Senescence remains active and knockouts of p53 targets, like Btg2, will occur in differentiated cells when they reach a affect the DNA damage-inducible G2/M arrest limited number of cell divisions (controlled by the length (Rouault et al., 1996). At the onset of differentiation, of telomeres) or upon activation of stress signals. Five the proliferation rate decreases with an extension of the major pathways have been identified that enable G1 phase, associated with the establishment of the transformed cells to escape senescence. These include Rb/E2F pathway regulating the G1/S checkpoint the telomerase, the p53, the Rb, the insulin-like growth (Figure 1b). Lack of Rb and p53 regulation affects cell factor (IGF)/Akt and the mitochondrial/oxidative stress differentiation and embryogenesis at several stages of pathways (reviewed by Miura et al. (2004); Campisi development, suggesting an essential role of these (2005)). Inappropriate inhibition or activation of these proteins in the maintenance of the proper balance pathways can lead to immortalization and are found between self-renewal and differentiation (reviewed by individually
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