REVIEW

Tumor suppressor p53: new functions of an old protein

  • Zhaohui FENG , 1 ,
  • Rui WU 1 ,
  • Meihua LIN 1 ,
  • Wenwei HU , 2
Expand
  • 1. Department of Radiation Oncology, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA
  • 2. Department of Pediatrics and Department of Obstetrics and Gynecology, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA

Received date: 30 Sep 2010

Accepted date: 02 Nov 2010

Published date: 01 Feb 2011

Copyright

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg

Abstract

p53 was discovered 30 years ago. Extensive studies have been done on p53 since then, which makes p53 one of the most extensively studied genes. p53 has long been recognized as a key tumor suppressor. Cell cycle arrest, apoptosis and senescence have been traditionally recognized as the main functions of p53 in tumor suppression. Recently, some novel functions of p53 have been identified, including the regulation of energy metabolism, antioxidant defense, and microRNA expression and maturation, which all contribute to the role of p53 in tumor suppression. Furthermore, the contribution of p53 to normal biologic processes (e.g. reproduction and aging) and some other aspects of diseases (e.g. neurodegenerative diseases) is only now being appreciated. Here we will review recent advances in the study of some new functions of p53.

Cite this article

Zhaohui FENG , Rui WU , Meihua LIN , Wenwei HU . Tumor suppressor p53: new functions of an old protein[J]. Frontiers in Biology, 2011 , 06(01) : 58 -68 . DOI: 10.1007/s11515-011-0970-8

Acknowledgements

Z. Feng is supported by the grant from National Institutes of Health (1R01CA143204-01) and New Jersey Commission on Cancer Research (09-1970-CCR-EO). W. Hu is supported by the grant from National Institutes of Health (1P30CA147892-01).
1
Bae B I, Xu H, Igarashi S, Fujimuro M, Agrawal N, Taya Y, Hayward S D, Moran T H, Montell C, Ross C A, Snyder S H, Sawa A (2005). p53 mediates cellular dysfunction and behavioral abnormalities in Huntington’s disease. Neuron, 47(1): 29–41

DOI PMID

2
Bartel D P (2009). MicroRNAs: target recognition and regulatory functions. Cell, 136(2): 215–233

DOI PMID

3
Benhar M, Engelberg D, Levitzki A (2002). ROS, stress-activated kinases and stress signaling in cancer. EMBO Rep, 3(5): 420–425

DOI PMID

4
Bensaad K, Tsuruta A, Selak M A, Vidal M N, Nakano K, Bartrons R, Gottlieb E, Vousden K H (2006). TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell, 126(1): 107–120

DOI PMID

5
Bensaad K, Vousden K H (2007). p53: new roles in metabolism. Trends Cell Biol, 17(6): 286–291

DOI PMID

6
Bond G L, Hu W, Bond E E, Robins H, Lutzker S G, Arva N C, Bargonetti J, Bartel F, Taubert H, Wuerl P, Onel K, Yip L, Hwang S J, Strong L C, Lozano G, Levine A J (2004). A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell, 119(5): 591–602

DOI PMID

7
Bond G L, Hu W, Levine A J (2005). MDM2 is a central node in the p53 pathway: 12 years and counting. Curr Cancer Drug Targets, 5(1): 3–8

DOI PMID

8
Bourdon A, Minai L, Serre V, Jais J P, Sarzi E, Aubert S, Chrétien D, de Lonlay P, Paquis-Flucklinger V, Arakawa H, Nakamura Y, Munnich A, Rötig A (2007). Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nat Genet, 39(6): 776–780

DOI PMID

9
Brooks C L, Gu W (2006). p53 ubiquitination: Mdm2 and beyond. Mol Cell, 21(3): 307–315

DOI PMID

10
Budanov A V, Karin M (2008). p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell, 134(3): 451–460

DOI PMID

11
Budanov A V, Sablina A A, Feinstein E, Koonin E V, Chumakov P M (2004). Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science, 304(5670): 596–600

DOI PMID

12
Calin G A, Croce C M (2006). MicroRNA signatures in human cancers. Nat Rev Cancer, 6(11): 857–866

DOI PMID

13
Chang T C, Wentzel E A, Kent O A, Ramachandran K, Mullendore M, Lee K H, Feldmann G, Yamakuchi M, Ferlito M, Lowenstein C J, Arking D E, Beer M A, Maitra A, Mendell J T (2007). Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell, 26(5): 745–752

DOI PMID

14
Choi J, Donehower L A (1999). p53 in embryonic development: maintaining a fine balance. Cell Mol Life Sci, 55(1): 38–47

DOI PMID

15
Chu F F, Esworthy R S, Chu P G, Longmate J A, Huycke M M, Wilczynski S, Doroshow J H (2004). Bacteria-induced intestinal cancer in mice with disrupted Gpx1 and Gpx2 genes. Cancer Res, 64(3): 962–968

DOI PMID

16
Crighton D, Wilkinson S, O’Prey J, Syed N, Smith P, Harrison P R, Gasco M, Garrone O, Crook T, Ryan K M (2006). DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell, 126(1): 121–134

DOI PMID

17
Donehower L A, Harvey M, Slagle B L, McArthur M J, Montgomery C A Jr, Butel J S, Bradley A (1992). Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature, 356(6366): 215–221

DOI PMID

18
Dröge W (2002). Free radicals in the physiological control of cell function. Physiol Rev, 82(1): 47–95

PMID

19
Duan W, Zhu X, Ladenheim B, Yu Q S, Guo Z, Oyler J, Cutler R G, Cadet J L, Greig N H, Mattson M P (2002). p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism. Ann Neurol, 52(5): 597–606

DOI PMID

20
el-Deiry W S, Kern S E, Pietenpol J A, Kinzler K W, Vogelstein B (1992). Definition of a consensus binding site for p53. Nat Genet, 1(1): 45–49

DOI PMID

21
Elchuri S, Oberley T D, Qi W, Eisenstein R S, Jackson Roberts L, Van Remmen H, Epstein C J, Huang T T (2005). CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene, 24(3): 367–380

DOI PMID

22
Feng Z (2010). p53 regulation of the IGF-1/AKT/mTOR pathways and the endosomal compartment. Cold Spring Harb Perspect Biol, 2(2): a001057

DOI PMID

23
Feng Z, Hu W, de Stanchina E, Teresky A K, Jin S, Lowe S, Levine A J (2007a). The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res, 67(7): 3043–3053

DOI PMID

24
Feng Z, Hu W, Rajagopal G, Levine A J (2008). The tumor suppressor p53: cancer and aging. Cell Cycle, 7(7): 842–847

DOI PMID

25
Feng Z, Hu W, Teresky A K, Hernando E, Cordon-Cardo C, Levine A J (2007b). Declining p53 function in the aging process: a possible mechanism for the increased tumor incidence in older populations. Proc Natl Acad Sci USA, 104(42): 16633–16638

DOI PMID

26
Feng Z, Jin S, Zupnick A, Hoh J, de Stanchina E, Lowe S, Prives C, Levine A J (2006). p53 tumor suppressor protein regulates the levels of huntingtin gene expression. Oncogene, 25(1): 1–7

PMID

27
Feng Z, Levine A J (2010). The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein. Trends Cell Biol, 20(7): 427–434

DOI PMID

28
Feng Z, Zhang H, Levine A J, Jin S (2005). The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA, 102(23): 8204–8209

DOI PMID

29
Fornari F, Gramantieri L, Giovannini C, Veronese A, Ferracin M, Sabbioni S, Calin G A, Grazi G L, Croce C M, Tavolari S, Chieco P, Negrini M, Bolondi L (2009). MiR-122/cyclin G1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinoma cells. Cancer Res, 69(14): 5761–5767

DOI PMID

30
Gambhir S S (2002). Molecular imaging of cancer with positron emission tomography. Nat Rev Cancer, 2(9): 683–693

DOI PMID

31
Garber K (2006). Energy deregulation: licensing tumors to grow. Science, 312(5777): 1158–1159

DOI PMID

32
Halliwell B (2007). Oxidative stress and cancer: have we moved forward? Biochem J, 401(1): 1–11

DOI PMID

33
Harris S L, Levine A J (2005). The p53 pathway: positive and negative feedback loops. Oncogene, 24(17): 2899–2908

DOI PMID

34
He L, He X, Lim L P, de Stanchina E, Xuan Z, Liang Y, Xue W, Zender L, Magnus J, Ridzon D, Jackson A L, Linsley P S, Chen C, Lowe S W, Cleary M A, Hannon G J (2007). A microRNA component of the p53 tumour suppressor network. Nature, 447(7148): 1130–1134

DOI PMID

35
Ho Y S, Xiong Y, Ma W, Spector A, Ho D S (2004). Mice lacking catalase develop normally but show differential sensitivity to oxidant tissue injury. J Biol Chem, 279(31): 32804–32812

DOI PMID

36
Hong H, Takahashi K, Ichisaka T, Aoi T, Kanagawa O, Nakagawa M, Okita K, Yamanaka S (2009). Suppression of induced pluripotent stem cell generation by the p53-21 pathway. Nature, 460(7259): 1132–1135

DOI PMID

37
Hsu P P, Sabatini D M (2008). Cancer cell metabolism: Warburg and beyond. Cell, 134(5): 703–707

DOI PMID

38
Hu W (2009). The role of p53 gene family in reproduction. Cold Spring Harb Perspect Biol, 1(6): a001073

DOI PMID

39
Hu W, Chan C S, Wu R, Zhang C, Sun Y, Song J S, Tang L H, Levine A J, Feng Z (2010a). Negative regulation of tumor suppressor p53 by microRNA miR-504. Mol Cell, 38(5): 689–699

DOI PMID

40
Hu W, Feng Z, Atwal G S, Levine A J (2008). p53: a new player in reproduction. Cell Cycle, 7(7): 848–852

DOI PMID

41
Hu W, Feng Z, Ma L, Wagner J, Rice J J, Stolovitzky G, Levine A J (2007a). A single nucleotide polymorphism in the MDM2 gene disrupts the oscillation of p53 and MDM2 levels in cells. Cancer Res, 67(6): 2757–2765

DOI PMID

42
Hu W, Feng Z, Teresky A K, Levine A J (2007b). p53 regulates maternal reproduction through LIF. Nature, 450(7170): 721–724

DOI PMID

43
Hu W, Zhang C, Wu R, Sun Y, Levine A, Feng Z (2010b). Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci USA, 107(16): 7455–7460

DOI PMID

44
Jacks T, Remington L, Williams B O, Schmitt E M, Halachmi S, Bronson R T, Weinberg R A (1994). Tumor spectrum analysis in p53-mutant mice. Curr Biol, 4(1): 1–7

DOI PMID

45
Jones R G, Plas D R, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum M J, Thompson C B (2005). AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell, 18(3): 283–293

DOI PMID

46
Kang H., Feng Z., Atwal G S, Sun Y, Murphy M E, Rebbeck T R, Rosenwaks Z, Levine A J, Hu W (2009). Single nucleotide polymorphisms in the p53 pathway regulate fertility in humans. Proc Natl Acad Sci U S A, 106(24): 9761–9766

DOI

47
Kawauchi K, Araki K, Tobiume K, Tanaka N (2008). p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. Nat Cell Biol, 10(5): 611–618

DOI PMID

48
Kay C, Jeyendran R S, Coulam C B (2006). p53 tumour suppressor gene polymorphism is associated with recurrent implantation failure. Reprod Biomed Online, 13(4): 492–496

DOI PMID

49
Kent O A, Mendell J T (2006). A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes. Oncogene, 25(46): 6188–6196

DOI PMID

50
Kondoh H, Lleonart M E, Gil J, Wang J, Degan P, Peters G, Martinez D, Carnero A, Beach D (2005). Glycolytic enzymes can modulate cellular life span. Cancer Res, 65(1): 177–185

PMID

51
Kulawiec M, Ayyasamy V, Singh K K (2009). p53 regulates mtDNA copy number and mitocheckpoint pathway. J Carcinog, 8(1): 8

DOI PMID

52
Lane D P, Cheok C F, Lain S (2010). p53-based cancer therapy. Cold Spring Harb Perspect Biol, 2(9): a001222

DOI PMID

53
Le M T, Teh C, Shyh-Chang N, Xie H, Zhou B, Korzh V, Lodish H F, Lim B (2009). MicroRNA-125b is a novel negative regulator of p53. Genes Dev, 23(7): 862–876

DOI PMID

54
Levine A J, Hu W, Feng Z (2006). The P53 pathway: what questions remain to be explored? Cell Death Differ, 13(6): 1027–1036

DOI PMID

55
Levine A J, Oren M (2009). The first 30 years of p53: growing ever more complex. Nat Rev Cancer, 9(10): 749–758

DOI PMID

56
Lim L P, Lau N C, Garrett-Engele P, Grimson A, Schelter J M, Castle J, Bartel D P, Linsley P S, Johnson J M (2005). Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature, 433(7027): 769–773

DOI PMID

57
Liu G, Chen X (2002). The ferredoxin reductase gene is regulated by the p53 family and sensitizes cells to oxidative stress-induced apoptosis. Oncogene, 21(47): 7195–7204

DOI PMID

58
Lu W, Ogasawara M A, Huang P (2007). Models of reactive oxygen species in cancer. Drug Discov Today Dis Models, 4(2): 67–73

DOI PMID

59
Lyakhov I G, Krishnamachari A, Schneider T D (2008). Discovery of novel tumor suppressor p53 response elements using information theory. Nucleic Acids Res, 36(11): 3828–3833

DOI PMID

60
Marión R M, Strati K, Li H, Murga M, Blanco R, Ortega S, Fernandez-Capetillo O, Serrano M, Blasco M A (2009). A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature, 460(7259): 1149–1153

DOI PMID

61
Martindale J L, Holbrook N J (2002). Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol, 192(1): 1–15

DOI PMID

62
Matoba S, Kang J G, Patino W D, Wragg A, Boehm M, Gavrilova O, Hurley P J, Bunz F, Hwang P M (2006). p53 regulates mitochondrial respiration. Science, 312(5780): 1650–1653

DOI PMID

63
Mendrysa S M, O’Leary K A, McElwee M K, Michalowski J, Eisenman R N, Powell D A, Perry M E (2006). Tumor suppression and normal aging in mice with constitutively high p53 activity. Genes Dev, 20(1): 16–21

DOI PMID

64
Minamino T, Orimo M, Shimizu I, Kunieda T, Yokoyama M, Ito T, Nojima A, Nabetani A, Oike Y, Matsubara H, Ishikawa F, Komuro I (2009). A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med, 15(9): 1082–1087

DOI PMID

65
Murphy M E (2006). Polymorphic variants in the p53 pathway. Cell Death Differ, 13(6): 916–920

DOI PMID

66
Neumann C A, Krause D S, Carman C V, Das S, Dubey D P, Abraham J L, Bronson R T, Fujiwara Y, Orkin S H, Van Etten R A (2003). Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression. Nature, 424(6948): 561–565

DOI PMID

67
Nicholls D (2002). Mitochondrial bioenergetics, aging, and aging-related disease. Sci SAGE KE, 2002(31): pe12

DOI PMID

68
Norimura T, Nomoto S, Katsuki M, Gondo Y, Kondo S (1996). p53-dependent apoptosis suppresses radiation-induced teratogenesis. Nat Med, 2(5): 577–580

DOI PMID

69
Olivier M, Hussain S P, Caron de Fromentel C, Hainaut P, Harris C C (2004). TP53 mutation spectra and load: a tool for generating hypotheses on the etiology of cancer. IARC Sci Publ, (157): 247–270

PMID

70
Park S Y, Lee J H, Ha M, Nam J W, Kim V N (2009). miR-29 miRNAs activate p53 by targeting p85 alpha and CDC42. Nat Struct Mol Biol, 16(1): 23–29

DOI PMID

71
Pillai R S, Bhattacharyya S N, Filipowicz W (2007). Repression of protein synthesis by miRNAs: how many mechanisms? Trends Cell Biol, 17(3): 118–126

DOI PMID

72
Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N, Bentwich Z, Oren M (2007). Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell, 26(5): 731–743

DOI PMID

73
Rivera A, Maxwell S A (2005). The p53-induced gene-6 (proline oxidase) mediates apoptosis through a calcineurin-dependent pathway. J Biol Chem, 280(32): 29346–29354

DOI PMID

74
Sablina A A, Budanov A V, Ilyinskaya G V, Agapova L S, Kravchenko J E, Chumakov P M (2005). The antioxidant function of the p53 tumor suppressor. Nat Med, 11(12): 1306–1313

DOI PMID

75
Sah V P, Attardi L D, Mulligan G J, Williams B O, Bronson R T, Jacks T (1995). A subset of p53-deficient embryos exhibit exencephaly. Nat Genet, 10(2): 175–180

DOI PMID

76
Scheffner M, Werness B A, Huibregtse J M, Levine A J, Howley P M (1990). The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell, 63(6): 1129–1136

DOI PMID

77
Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E (2004). The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res, 64(7): 2627–2633

DOI PMID

78
Strong L C (2003). General keynote: Hereditary cancer: lessons from Li-Fraumeni sydrome. Gyuecol Oncol, 88(part 2): S4–S7j discussion S11–S13<DOI OutputMedium="All"/><PubMed OutputMedium="All"/>

78
Suzuki H I, Yamagata K, Sugimoto K, Iwamoto T, Kato S, Miyazono K (2009). Modulation of microRNA processing by p53. Nature, 460(7254): 529–533

DOI PMID

79
Suzuki S, Tanaka T, Poyurovsky M V, 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 (2010). Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci USA, 107(16): 7461–7466

DOI PMID

80
Tan M, Li S, Swaroop M, Guan K, Oberley L W, Sun Y (1999). Transcriptional activation of the human glutathione peroxidase promoter by p53. J Biol Chem, 274(17): 12061–12066

DOI PMID

81
Tazawa H, Tsuchiya N, Izumiya M, Nakagama H (2007). Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci USA, 104(39): 15472–15477

DOI PMID

82
Teodoro J G, Evans S K, Green M R (2007). Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome. J Mol Med, 85(11): 1175–1186

DOI PMID

83
Teodoro J G, Parker A E, Zhu X, Green M R (2006). p53-mediated inhibition of angiogenesis through up-regulation of a collagen prolyl hydroxylase. Science, 313(5789): 968–971

DOI PMID

84
Tyner S D, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C, Hee Park S, Thompson T, Karsenty G, Bradley A, Donehower L A (2002). p53 mutant mice that display early ageing-associated phenotypes. Nature, 415(6867): 45–53

DOI PMID

85
Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe S R, Alderson N L, Baynes J W, Epstein C J, Huang T T, Nelson J, Strong R, Richardson A (2003). Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics, 16(1): 29–37

DOI PMID

86
Vassilev L T (2007). MDM2 inhibitors for cancer therapy. Trends Mol Med, 13(1): 23–31

DOI PMID

87
Vassilev L T, Vu B T, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu E A (2004). In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science, 303(5659): 844–848

DOI PMID

88
Ventura A, Kirsch D G, McLaughlin M E, Tuveson D A, Grimm J, Lintault L, Newman J, Reczek E E, Weissleder R, Jacks T (2007). Restoration of p53 function leads to tumour regression in vivo. Nature, 445(7128): 661–665

DOI PMID

89
Vousden K H, Prives C (2009). Blinded by the light: The growing complexity of p53. Cell, 137(3): 413–431

DOI PMID

90
Wade M, Wahl G M (2009). Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry? Mol Cancer Res, 7(1): 1–11

DOI PMID

91
Warburg O (1956). On the origin of cancer cells. Science, 123(3191): 309–314

DOI PMID

92
Xue W, Zender L, Miething C, Dickins R A, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe S W (2007). Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature, 445(7128): 656–660

DOI PMID

93
Yamakuchi M, Ferlito M, Lowenstein C J (2008). miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci USA, 105(36): 13421–13426

DOI PMID

94
Yee K S, Wilkinson S, James J, Ryan K M, Vousden K H (2009). PUMA- and Bax-induced autophagy contributes to apoptosis. Cell Death Differ, 16(8): 1135–1145

DOI PMID

95
Yoon K A, Nakamura Y, Arakawa H (2004). Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses. J Hum Genet, 49(3): 134–140

DOI PMID

96
Zhou B P, Liao Y, Xia W, Zou Y, Spohn B, Hung M C (2001). HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol, 3(11): 973–982

DOI PMID

Outlines

/