21. Webley K, Bond JA, Jones CJ, Blaydes JP, Craig A, et al. (2000) Posttranslational modifications of p53 in replicative senescence overlapping but distinct from those induced by DNA damage. Mol Cell Biol 20: 2803–2808. 22. Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, et al. (2000) p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46- phosphorylated p53. Cell 102: 849–862. 23. Ferbeyre G, de Stanchina E, Querido E, Baptiste N, Prives C, et al. (2000) PML is induced by oncogenic ras and promotes premature senescence. Genes Dev 14: 2015–2027. 24. Lowe SW, Ruley HE, Jacks T, Housman DE (1993) p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74: 957–967. 25. Tanaka N, Ishihara M, Lamphier MS, Nozawa H, Matsuyama T, et al. (1996) Cooperation of the tumour suppressors IRF-1 and p53 in response to DNA damage. Nature 382: 816–818. 26. Castro ME, del Valle Guijarro M, Moneo V, Carnero A (2004) Cellular senescence induced by p53-ras cooperation is independent of p21waf1 in murine embryo fibroblasts. J Cell Biochem 92: 514–524. 27. Narita M, Nunez S, Heard E, Lin AW, Hearn SA, et al. (2003) Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113: 703–716. 28. Michalovitz D, Halevy O, Oren M (1990) Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53. Cell 62: 671–680. 29. Nelson DA, Krucher NA, Ludlow JW (1997) High molecular weight protein phosphatase type 1 dephosphorylates the retinoblastoma protein. J Biol Chem 272: 4528–4535. 30. Alberts AS, Thorburn AM, Shenolikar S, Mumby MC, Feramisco JR (1993) Regulation of cell cycle progression and nuclear affinity of the retinoblastoma protein by protein phosphatases. Proc Natl Acad Sci U S A 90: 388–392. 31. Berndt N, Dohadwala M, Liu CW (1997) Constitutively active protein phosphatase 1alpha causes Rb-dependent G1 arrest in human cancer cells. Curr Biol 7: 375–386. 32. Rubin E, Tamrakar S, Ludlow JW (1998) Protein phosphatase type 1, the product of the retinoblastoma susceptibility gene, and cell cycle control. Front Biosci 3: D1209–1219. 33. Mooi WJ, Peeper DS (2006) Oncogene-induced cell senescence–halting on the road to cancer. N Engl J Med 355: 1037–1046. 34. Ayllon V, Martinez AC, Garcia A, Cayla X, Rebollo A (2000) Protein phosphatase 1alpha is a Ras-activated Bad phosphatase that regulates interleukin-2 deprivation-induced apoptosis. Embo J 19: 2237–2246. 35. Sherr CJ, McCormick F (2002) The RB and p53 pathways in cancer. Cancer Cell 2: 103–112. 36. Weber JD, Jeffers JR, Rehg JE, Randle DH, Lozano G, et al. (2000) p53- independent functions of the p19(ARF) tumor suppressor. Genes Dev 14: 2358–2365. 37. Palmero I, Pantoja C, Serrano M (1998) p19ARF links the tumour suppressor p53 to Ras. Nature 395: 125–126. 38. Efeyan A, Garcia-Cao I, Herranz D, Velasco-Miguel S, Serrano M (2006) Tumour biology: Policing of oncogene activity by p53. Nature 443: 159. 39. Martins CP, Brown-Swigart L, Evan GI (2006) Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 127: 1323–1334. p53 Response to Senescence 40. Christophorou MA, Martin-Zanca D, Soucek L, Lawlor ER, Brown-Swigart L, et al. (2005) Temporal dissection of p53 function in vitro and in vivo. Nat Genet 37: 718–726. 41. Campisi J (2005) Suppressing cancer: the importance of being senescent. Science 309: 886–887. 42. Collado M, Serrano M (2005) The senescent side of tumor suppression. Cell Cycle 4: 1722–1724. 43. Evan GI, Christophorou M, Lawlor EA, Ringshausen I, Prescott J, et al. (2005) Oncogene-dependent tumor suppression: using the dark side of the force for cancer therapy. Cold Spring Harb Symp Quant Biol 70: 263–273. 44. Carnero A, Hudson JD, Hannon GJ, Beach DH (2000) Loss-of-function genetics in mammalian cells: the p53 tumor suppressor model. Nucleic Acids Res 28: 2234–2241. 45. Dimri GP, Lee X, Basile G, Acosta M, Scott G, et al. (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 92: 9363–9367. 46. Zou H, Hastie T (2005) Regularization and variable selection via the elastic net. J ROY STAT SOC SER B-STAT MET 67: 301–320. 47. Daubechies I, Defrise M, De Mol C (2004) An iterative thresholding algorithm for linear inverse problems with a sparsity constraint. Communications on Pure and Applied Mathematics 57: 1413–1457. 48. McPherson JP, Tamblyn L, Elia A, Migon E, Shehabeldin A, et al. (2004) Lats2/ Kpm is required for embryonic development, proliferation control and genomic integrity.EMBO J 23: 3677–88. 49. Aylon Y, Michael D, Shmueli A, Yabuta N, Nojima H, Oren M (2006) A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization. Genes Dev 20: 2687–700. 50. Voorhoeve PM, le Sage C, Schrier M, Gillis AJ, Stoop H, et al. (2006) A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell 124: 1169–81. 51. Takahashi Y, Miyoshi Y, Takahata C, Irahara N, Taguchi T, et al. (2005) Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers. Clin Cancer Res 11: 1380–5. 52. Jime´nez-Velasco A, Roma´n-Go´mez J, Agirre X, Barrios M, Navarro G, et al. (2005) Downregulation of the large tumor suppressor 2 (LATS2/KPM) gene is associated with poor prognosis in acute lymphoblastic leukemia. Leukemia 19: 2347–50. 53. Sun A, Bagella L, Tutton S, Romano G, Giordano A (2007) From G0 to S phase: a view of the roles played by the retinoblastoma (Rb) family members in the Rb-E2F pathway. J Cell Biochem 102: 1400–4. 54. Vidal A, Carneiro C, Zalvide JB (2007) Of mice without pockets: mouse models to study the function of Rb family proteins. Front Biosci 12: 4483–96. 55. Goodrich DW (2006) The retinoblastoma tumor-suppressor gene, the exception that proves the rule. Oncogene 25: 5233–43. 56. Bringold F, Serrano M (2000) Tumor suppressors and oncogenes in cellular senescence. Exp Gerontol 35: 317–29. 57. Rajesh D, Schell K, Verma AK (1999) Ras mutation, irrespective of cell type and p53 status, determines a cell’s destiny to undergo apoptosis by okadaic acid, an inhibitor of protein phosphatase 1 and 2A. Mol Pharmacol 56: 515–25. PLoS ONE | www.plosone.org 14 September 2008 | Volume 3 | Issue 9 | e3230