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Aging (Albany NY). 2010 June; 2(6): 344–352.
Published online 2010 June 25. doi:  10.18632/aging.100160
PMCID: PMC2919254

The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway


Transient induction of p53 can cause reversible quiescence and irreversible senescence. Using nutlin-3a (a small molecule that activates p53 without causing DNA damage), we have previously identified cell lines in which nutlin-3a caused quiescence. Importantly, nutlin-3a caused quiescence by actively suppressing the senescence program (while still causing cell cycle arrest). Noteworthy, in these cells nutlin-3a inhibited the mTOR (mammalian Target of Rapamycin) pathway, which is known to be involved in the senescence program. Here we showed that shRNA-mediated knockdown of TSC2, a negative regulator of mTOR, partially converted quiescence into senescence in these nutlin-arrested cells. In accord, in melanoma cell lines and mouse embryo fibroblasts, which easily undergo senescence in response to p53 activation, nutlin-3a failed to inhibit mTOR. In these senescence-prone cells, the mTOR inhibitor rapamycin converted nutlin-3a-induced senescence into quiescence. We conclude that status of the mTOR pathway can determine, at least in part, the choice between senescence and quiescence in p53-arrested cells.

Keywords: p53, senescence, rapamycin, mTOR, cancer, cell cycle


Depending on the cell type and other factors p53 activation can result in apoptosis, reversible (quiescence) and irreversible (senescence) cell cycle arrest [1-8]. While the choice between apoptosis and cell cycle arrest has been intensively scrutinized, the choice between quiescence and senescence was not systematically addressed and remains elusive. In order to observe whether p53 activation causes either senescence or quiescence, others and we employed nutlin-3a. Nutlin-3a, a small molecular therapeutic, inhibits Mdm2/p53 interaction and induces p53 at physiological levels without causing DNA damage [9-11]. It was reported that nutlin-3a caused senescent morphology and permanent loss of proliferative potential [12,13]. However, in other cell lines nutlin-3a caused quiescence so that cells resumed proliferation, when nutlin-3a was removed [14-16]. Moreover, we recently reported that in human fibroblasts (WI-38tert) and fibrosarcoma cells (HT-1080-p21-9), in which nutlin-3a caused quiescence [16], p53 acted as a suppressor of senescence [17]. Thus, ectopic expression of p21 in these cells caused senescence, while simultaneous induction of p53 converted senescence into quiescence [17]. In agreement with previous reports [18-20], we found that p53 inhibited the mTOR pathway [17]. Importantly, the mTOR pathway is involved in cellular senescence [21-26]. We suggested that p53-mediated arrest remains reversible as long as p53 inhibits mTOR. If this model is correct, then senescence would occur in those cells, in which p53 is incapable of suppressing mTOR. Here we provide experimental evidence supporting this prediction and demonstrate that irreversibility of p53-mediated arrest may result from its failure to suppress the mTOR pathway.


Depletion of TSC2 favors senescence by p53

We have shown that nutlin-3a caused quiescence in HT-p21-9 cells and WI-38tert cells [16]. In these cells, nutlin-3a actively suppressed senescence and this suppression was associated with inhibition of the mTOR pathway by p53 [17]. Next, we investigated whether nutlin-3a can cause senescence in cells lacking tuberous sclerosis 2 (TSC2) (Figure (Figure1A), 1A), given that regulation of mTOR by p53 requires TSC2 [18]. The transduced cells were transiently treated with nutlin-3a as shown (Figure (Figure1B).1B). The Tsc2-depleted cells acquired a large/flat morphology and could not resume proliferation, whereas cells treated with vector and nutlin-3a did not become senescent and resumed proliferation, forming colonies after removal of nutlin-3a (Figure (Figure1C-D).1C-D). The potency of shTSC2 with different sequences varied and two other shTSC2 were less potent but still depleted TSC2 at some time points (Supplemental Figure Figure1)1) and partially decreased the proliferative potential in nutlin-3a-arrested cells (Supplemental Figure Figure1). 1).

Figure 1.
Depletion of TSC2 converts quiescence into senescence in HT-p21-9 cells.

We next extended this observation to WI-38tert cells transduced with shTSC2 (Figure (Figure2A).2A). In control, nutlin- 3a caused a lean morphology, a characteristic of quiescence [16]. Depletion of TSC2 by shTSC2 converted quiescent morphology to senescent morphology (Figure (Figure2B).2B). Furthermore, this was associated with permanent loss of proliferative potential (Figure (Figure2C).2C). In control, cells resumed proliferation after removal of nutlin-3a, whereas nutlin-3a caused permanent loss of proliferative potential in shTSC2-treated cells (Figure (Figure2C).2C). In agreement with our results, it was previously observed that knockout of Tsc2 cooperates with p53 in induction of cellular senescence in MEFs [27].

Figure 2.
Depletion of TSC2 converts quiescence into senescence in WI-38tert cells.

Nutlin-3 causes senescence in Mel-10 and -9 cells

We next wished to identify senescence-prone cells, which undergo senescence in response to nutlin-3a. In MEL-10 and Mel-9, two melanoma-derived cell lines, nutlin-3a induced p53 and p21 (Figure (Figure3A)3A) and caused senescent morphology (Figure (Figure3B)3B) and cells did not resume proliferation, when nutlin-3a was removed (Supplemental Figure Figure2).2). In contrast, rapamycin did not cause senescent morphology and cells resumed proliferation, when rapamycin was removed (Figure (Figure3B3B and Supplemental Figure Figure2).2). Unlike rapamycin, nutlin-3a did not inhibit S6 phosphorylation (Figure (Figure3A), 3A), a marker of rapamycin-sensitive mTOR activity.

Figure 3.
Effects of nutlin-3a and rapamycin on melanoma cells.

Rapamycin suppresses nutlin-3a-induced senescence

To establish a causal link between mTOR and senescence, we next investigated whether inhibition of the mTOR pathway by rapamycin could convert nutlin-3a-induced senescence into quiescence. Rapamycin did not affect p53 and p21 induction caused by nutlin-3a but abrogated S6 phosphorylation (Figure (Figure4A),4A), associated with conversion from senescent morphology to quiescent morphology (Figure (Figure4B).4B). Importantly, cells were capable to resume proliferation following removal of nutlin-3a and rapamycin, indicating that the condition was reversible (Figure (Figure4C).4C). Similar results were obtained with Mel-9 cells (data not shown).

Figure 4.
EEffect of rapamycin on nutlin-induced senescence in melanoma cells.

Next, we extended this observation to cells of different tissue and species origin. As shown previously, nutlin-3a caused senescence in mouse embryonic fibroblasts (MEFs) [13]. Here we showed that nulin-3a failed to inhibit mTOR pathway in MEF (Figure (Figure5A),5A), and caused senescence (Figure (Figure5B).5B). Rapamycin inhibited the mTOR pathway and converted senescent morphology to quiescent morphology (Figure (Figure5).5). This suggests that failure to suppress a rapamycin-sensitive pathway determines nutlin-3a-induced senescence instead of quiescence.

Figure 5.
Effect of rapamycin on nutlin-induced senescence in melanoma cells . (A.


The role of p53 in organismal aging and longevity is complex [28-32], indicating that p53 may act as anti-aging factor in some conditions. We have recently demonstrated that p53 can suppress cellular senescence, converting it into quiescence [17]. In these quiescence-prone cells, p53 inhibited the mTOR pathway, which is involved in senescence program (Figure (Figure6A). 6A). Still p53 induces senescence in numerous cell types. Here we showed that in those cell types, in which nutlin-3a caused senescence, it failed to inhibit the mTOR pathway (Figure (Figure6B).6B). The role of active mTOR as a senescence-inducing factor in these cells was demonstrated by using rapamycin, which partially converted nutlin-3a-induced senescence into quiescence (Figure (Figure6B,6B, lower panel). This indicates that rapamycin-sensitive mTOR activity is necessary for senescence during nutlin-3a-induced cell cycle arrest. And vice versa, in quiescence-prone cells, depletion of TSC2 converted quiescence into senescence (Figure (Figure6A,6A, lower panel). Taken together, data suggest that activation of the mTOR pathway favors senescence (Figure (Figure7).7). In agreement, Ras accelerated senescence in nutlin-arrested cells [13]. Similarly, activation of Ras and MEK in murine fibroblasts converted p53-induced quiescence into senescence [33]. Interestingly, p53 levels did not correlate with the senescence phenotype, suggesting that factors other than p53 may determine senescence [33]. These important observations are in agreement with our model that senescence requires two factors: cell cycle arrest caused by p53 and simultaneous activation of the growth-promoting mTOR pathway (Note: Ras is an activator of the mTOR pathway). And vice versa it was observed that induction of p53 maintains quiescence upon serum starvation, without causing senescence [34]. In agreement, our model predicts that, by deactivating mTOR, serum starvation prevents senescence.

Figure 6.
p53 causes senescence by failing to suppress senescence.
Figure 7.
Activation of the mTOR pathway favors senescence in nutlin-3a-arrested cells.

Another factor that favors senescence is the duration of cell cycle arrest [13,35]. Importantly, the duration of the arrest may exceed the duration of treatment with nutlin-3a because of persistent induction of p21 even after removal of nutlin-3a in some cancer cell lines [35]. Additional pathways may be involved in the senescence program. For example, nutlin-3a induces cytoskeletal rearrangement [36]. We speculate that p53 affects not only rapamycin-sensitive mTORC1 but also the mTORC2 complex, given that mTORC2 controls the actin cytoskeleton [37]. Also, p53 inhibits downstream branches of the mTOR pathway [38,39]. P53 stimulates autophagy [18,40], which in turn is essential for life-extension by pharmacological manipulations (see [41-44]). Finally, p53 affects cellular metabolism [45-48] and this effect may contribute to suppression of cellular senescence and synergistically potentate metabolic changes caused by mTOR inhibition. The relative contribution of all these mutually dependent factors needs further investigations. The key role of mTOR in cellular senescence links cellular and organismal aging and age-related diseases.

Material and methods

Cell lines and reagents. HT-p21-9 cells are derivatives of HT1080 human fibrosarcoma cells, where p21 expression can be turned on or off using a physiologically neutral agent isopropyl--thio-galactosidase (IPTG) [16,49-51]. HT-p21-9 cells express GFP. WI-38-Tert, WI-38 fibroblasts immortalized by telomerase were described previously [16,17]. Melanoma cell lines, MEL-9 (SK-Mel-103) and MEL-10 (SK-Mel-147), were described previously [52,53]. RPE cells were described previously [21,22]. MEF, mouse fibroblasts isolated from 13-day embryos, were provided by Marina Antoch (RPCI) and maintained in DMEM supplemented with 10% FCS. Rapamycin (LC Laboratories, MA, USA), IPTG (Sigma- Aldrich, St. Louis, MO), nutlin-3a (Sigma-Aldrich) were used as previously described [17].

Lentiviral shRNA construction . Bacterial glycerol stocks [clone NM_000548.2-1437s1c1 (#10), NM_000548.x-4581s1c1 (#7) and NM_000548.2-4551s1c1 (#9)] containing lentivirus plasmid vector pLKO.1-puro with shRNA specific for TSC2 was purchased from Sigma. The targeting sequences are: CCGGGCTCATCAACAGGCAGTTCTACTCGAGTAGAACTGCCTGTTGATGAGCTTTTTG (#10), CCGG CAATGAGTCACAGTCCTTTGACTCGAGTCAAAGGACTGTGACTCATTGTTTTTG (#7) and CCGGCGACGAGTCAAACAAGCCAATCTCGAGATTGGCTTGTTTGACTCGTCGTTTTTG (#9).

pLKO.1-puro lentiviral vector without shRNA was used as a control. Lentiviruses were produced in HEK293T cells after co-transfection of lentivirus plasmid vector with shRNA or control vector with packaging plasmids using Lipofectamine2000 (Invitrogen). After 48h and 72h medium containing lentivirus was collected, centrifuged at 2000g and filtered through 0.22 uM filter. Filtered virus containing medium was used for cell infection or stored at -80 C. Cells were transduced with lentivirus in the presence of 8 mg/ml polybrene and selected with puromycin (1-2 mg/ml) for 4-6 days. Cells were treated with drugs either 24h after transduction or after puromycin selection for infected cells.

Colony formation assay. Plates were fixed and stained with 1.0 % crystal violet (Sigma-Aldrich).

Immunoblot analysis. The following antibodies were used: anti-p53 and anti-p21 antibodies from Cell signaling and anti-actin antibodies from Santa Cruz Biotechnology, rabbit anti-phospho-S6 (Ser240/244) and (Ser235/236), mouse anti-S6, mouse anti-phospho- p70 S6 kinase (Thr389), mouse anti-p21, rabbit anti-phospho-4E-BP1 (Thr37/46) from Cell Signaling; mouse anti-4E-BP1 from Invitrogen; mouse anti-p53 (Ab-6) from Calbiochem.

Beta-galactosidase staining. beta-Gal staining was performed using Senescence -galactosidase staining kit (Cell Signaling Technology) according to manufacturer's protocol.

Supplementary figures

Supplementary Figure 1

Depletion of TSC2 converts quiescence into senescence in HT-p21-9 cells.

(A) HT-p21-9 cells were transduced with control lentivirus (pLKO) or lentivirus expressing shTSC2 (sequence # 7, 8, 9) and selected with puromycin for 10 days and then immunoblot was performed. (B) HT-p21-9 cells were transduced with control pLKO or shTSC2 (and selected for 4 days with puromycin). Then 1000 cells were plated per 60-mm dishes and, the next day, were treated with nutlin-3a for 3 days. Then nutlin-3a was washed out and cells were cultivated in fresh medium for 8 days. Colonies were stained with crystal violet.

Supplementary Figure 2

Irreversible and reversible effects of nutlin-3a and rapamycin:.

Mel-10 and Mel-9 cells were incubated with 10 uM nutlin (N) and 500 nM rapamycin (R) for 4 day and then nutlin-3a was washed. After a week, cells were counted.


The authors of this manuscript have no conflict of interests to declare.


1. Vogelstein B, Lane DP, Levine AJ. Surfing the p53 network. Nature. 2000;408:307–310. [PubMed]
2. Itahana K, Dimri G, Campisi J. Regulation of cellular senescence by p53. Eur J Biochem. 2001;268:2784–2791. [PubMed]
3. Vousden KH. Outcomes of p53 activation--spoilt for choice. J Cell Sci. 2006;119:5015–5020. [PubMed]
4. Vousden KH, Prives C. Blinded by the Light: The Growing Complexity of p53. Cell. 2009;137:413–431. [PubMed]
5. Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 2009;9:749–758. [PMC free article] [PubMed]
6. Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer. 2009;9:862–873. [PubMed]
7. Liebermann DA, Hoffman B, Vesely D. p53 induced growth arrest versus apoptosis and its modulation by survival cytokines. Cell Cycle. 2007;6:166–170. [PubMed]
8. Paris R, Henry RE, Stephens SJ, McBryde M, Espinosa JM. Multiple p53-independent gene silencing mechanisms define the cellular response to p53 activation. Cell Cycle. 2008;7:2427–2433. [PMC free article] [PubMed]
9. Vassilev LT. Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics. Cell Cycle. 2004;3:419–421. [PubMed]
10. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303:844–848. [PubMed]
11. Huang B, Vassilev LT. Reduced transcriptional activity in the p53 pathway of senescent cells revealed by the MDM2 antagonist nutlin-3. Aging. 2009;1:845–854. [PMC free article] [PubMed]
12. Van Maerken T, Speleman F, Vermeulen J, Lambertz I, De Clercq S, De Smet E, Yigit N, Coppens V, Philippé J, De Paepe A, Marine JC, Vandesompele J. Small-molecule MDM2 antagonists as a new therapy concept for neuroblastoma. Cancer Res. 2006;66:9646–9655. [PubMed]
13. Efeyan A, Ortega-Molina A, Velasco-Miguel S, Herranz D, Vassilev LT, Serrano M. Induction of p53-dependent senescence by the MDM2 antagonist nutlin-3a in mouse cells of fibroblast origin. Cancer Res. 2007;67:7350–7357. [PubMed]
14. Huang B, Deo D, Xia M, Vassilev LT. Pharmacologic p53 Activation Blocks Cell Cycle Progression but Fails to Induce Senescence in Epithelial Cancer Cells. Mol Cancer Res. 2009;7:1497–1509. [PubMed]
15. Cheok CF, Kua N, Kaldis P, Lane DP. Combination of nutlin-3 and VX-680 selectively targets p53 mutant cells with reversible effects on cells expressing wild-type p53. Cell Death Differ. 2010 In press . [PubMed]
16. Korotchkina LG, Demidenko ZN, Gudkov AV, Blagosklonny MV. Cellular quiescence caused by the Mdm2 inhibitor nutlin-3a. Cell Cycle. 2009;8:3777–3781. [PubMed]
17. Demidenko ZN, Korotchkina LG, Gudkov AV, Blagosklonny MV. Paradoxical suppression of cellular senescence by p53. Proc Natl Acad Sci U S A. 2010;9660-4:9660–9664. [PubMed]
18. Feng Z, Zhang H, Levine AJ, Jin S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A. 2005;102:8204–8209. [PubMed]
19. Budanov AV, Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell. 2008;134:451–460. [PMC free article] [PubMed]
20. Matthew EM, Hart LS, Astrinidis A, Navaraj A, Dolloff NG, Dicker DT, Henske EP, El-Deiry WS. The p53 target Plk2 interacts with TSC proteins impacting mTOR signaling, tumor growth and chemosensitivity under hypoxic conditions. Cell Cycle. 2009;8:4168–4175. [PMC free article] [PubMed]
21. Demidenko ZN, Blagosklonny MV. Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle. 2008;7:3355–3361. [PubMed]
22. Demidenko ZN, Zubova SG, Bukreeva EI, Pospelov VA, Pospelova TV, Blagosklonny MV. Rapamycin decelerates cellular senescence. Cell Cycle. 2009;8:1888–1895. [PubMed]
23. Demidenko ZN, Shtutman M, Blagosklonny MV. Pharmacologic inhibition of MEK and PI-3K converges on the mTOR/S6 pathway to decelerate cellular senescence. Cell Cycle. 2009;8:1896–1900. [PubMed]
24. Demidenko ZN, Blagosklonny MV. At concentrations that inhibit mTOR, resveratrol suppresses cellular senescence. Cell Cycle. 2009;8:1901–1904. [PubMed]
25. Demidenko ZN, Blagosklonny MV. Quantifying pharma-cologic suppression of cellular senescence: prevention of cellular hypertrophy versus preservation of proliferative potential. Aging. 2009;1:1008–1016. [PMC free article] [PubMed]
26. Pospelova TV, Demidenko ZN, Bukreeva EI, Pospelov VA, Gudkov AV, Blagosklonny MV. Pseudo-DNA damage response in senescent cells. Cell Cycle. 2009;8:4112–4118. [PMC free article] [PubMed]
27. Zhang H, Cicchetti G, Onda H, Koon HB, Asrican K, Bajraszewski N, Vazquez F, Carpenter CL, Kwiatkowski DJ. Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. J Clin Invest. 2003;112:1223–1233. [PMC free article] [PubMed]
28. Matheu A, Maraver A, Klatt P, Flores I, Garcia-Cao I, Borras C, Flores JM, Vina J, Blasco MA, Serrano M. Delayed ageing through damage protection by the Arf/p53 pathway. Nature. 2007;448:375–379. [PubMed]
29. Waskar M, Landis GN, Shen J, Curtis C, Tozer K, Abdueva D, Skvortsov D, Tavare S, Tower J. Drosophila melanogaster p53 has developmental stage-specific and sex-specific effects on adult life span indicative of sexual antagonistic pleiotropy. Aging. 2009;1:903–936. [PMC free article] [PubMed]
30. Biteau B, Jasper H. It's all about balance: p53 and aging. Aging. 2009;1:884–886. [PMC free article] [PubMed]
31. Hur JH, Walker DW. p53, sex, and aging: lessons from the fruit fly. Aging. 2009;1:881–883. [PMC free article] [PubMed]
32. Donehower LA. Longevity regulation in flies: a role for p53. Aging. 2009;1:6–8. [PMC free article] [PubMed]
33. Ferbeyre G, de Stanchina E, Lin AW, Querido E, McCurrach ME, Hannon GJ, Lowe SW. Oncogenic ras and p53 cooperate to induce cellular senescence. Mol Cell Biol. 2002;22:3497–3508. [PMC free article] [PubMed]
34. Itahana K, Dimri GP, Hara E, Itahana Y, Zou Y, Desprez PY, Campisi J. A role for p53 in maintaining and establishing the quiescence growth arrest in human cells. J Biol Chem. 2002;277:18206–18214. [PubMed]
35. Shen H, Maki CG. Persistent p21 expression after Nutlin-3a removal is associated with senescence-like arrest in 4N cells. J Biol Chem. 2010;285:23105–23114. [PMC free article] [PubMed]
36. Moran DM, Maki CG. Nutlin-3a induces cytoskeletal rearrangement and inhibits the migration and invasion capacity of p53 wild-type cancer cells. Mol Cancer Ther. 2010;9:895–905. [PMC free article] [PubMed]
37. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6:1122–1128. [PubMed]
38. Constantinou C, Clemens MJ. Regulation of the phosphorylation and integrity of protein synthesis initiation factor eIF4GI and the translational repressor 4E-BP1 by p53. Oncogene. 2005;24:4839–4850. [PubMed]
39. Constantinou C, Elia A, Clemens MJ. Activation of p53 stimulates proteasome-dependent truncation of eIF4E-binding protein 1 (4E-BP1) Biol Cell. 2008;100:279–289. [PubMed]
40. Maiuri MC, Malik SA, Morselli E, Kepp O, Criollo A, Mouchel PL, Carnuccio R, Kroemer G. Stimulation of autophagy by the p53 target gene Sestrin2. Cell Cycle. 2009;8:1571–1576. [PubMed]
41. Morselli E, Galluzzi L, Kepp O, Criollo A, Maiuri MC, Tavernarakis N, Madeo F, Kroemer G. Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol. Aging. 2009;1:961–970. [PMC free article] [PubMed]
42. Alvers AL, Wood MS, Hu D, Kaywell AC, Dunn WA Jr, Aris JP. Autophagy is required for extension of yeast chronological life span by rapamycin. Autophagy. 2009;5:847–849. [PMC free article] [PubMed]
43. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, Partridge L. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010;11:35–46. [PMC free article] [PubMed]
44. Hands SL, Proud CG, Wyttenbach A. mTOR's role in ageing: protein synthesis or autophagy. Aging. 2009:586–597. [PMC free article] [PubMed]
45. Vousden KH, Ryan KM. p53 and metabolism. Nat Rev Cancer. 2009;9:691–700. [PubMed]
46. Feng Z, Levine AJ. The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein. Trends Cell Biol. 2010 [PMC free article] [PubMed]
47. Hu W, Zhang C, Wu R, Sun Y, Levine A, Feng Z. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci U S A. 2010;107:7455–7460. [PubMed]
48. Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, Lokshin M, Hosokawa H, Nakayama T, Suzuki Y, Sugano S, Sato E, Nagao T, Yokote K, Tatsuno I, Prives C. Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci U S A. 2010;107:7461–7466. [PubMed]
49. Chang BD, Broude EV, Dokmanovic M, Zhu H, Ruth A, Xuan Y, Kandel ES, Lausch E, Christov K, Roninson IB. A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res. 1999;59:3761–3767. [PubMed]
50. Chang BD, Broude EV, Fang J, Kalinichenko TV, Abdryashitov R, Poole JC, Roninson IB. p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells. Oncogene. 2000;19:2165–2170. [PubMed]
51. Broude EV, Swift ME, Vivo C, Chang BD, Davis BM, Kalurupalle S, Blagosklonny MV, Roninson IB. p21(Waf1/Cip1/Sdi1) mediates retinoblastoma protein degradation. Oncogene. 2007;26:6954–6958. [PubMed]
52. Mannava S, Grachtchouk V, Wheeler LJ, Im M, Zhuang D, Slavina EG, Mathews CK, Shewach DS, Nikiforov MA. Direct role of nucleotide metabolism in C-MYC-dependent proliferation of melanoma cells. Cell Cycle. 2008;7:2392–2400. [PMC free article] [PubMed]
53. Zhuang D, Mannava S, Grachtchouk V, Tang WH, Patil S, Wawrzyniak JA, Berman AE, Giordano TJ, Prochownik EV, Soengas MS, Nikiforov MA. C-MYC overexpression is required for continuous suppression of oncogene-induced senescence in melanoma cells. Oncogene. 2008;27:6623–6634. [PMC free article] [PubMed]

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