"The promises and perils of p53".
Valery Krizhanovsky and Scott W. Lowe
Valery Krizhanovsky and Scott W. Lowe are in the Cold Spring Harbor
Laboratory and Howard
Hughes Medical Institute, Cold Spring Harbor, New York 11724, USA.
e-mails: krizh@cshl.edu; lowe@cshl.edu
Mutations that inactivate the p53 tumour suppressor-protein network
occur in most human cancers and, consequently, the roles and regulation
of p53 activity in tumour formation are the topic of intense research.
Inherited germline mutations in the p53 gene promote cancer in mice
and humans, and p53 loss interacts with various mutant genes to transform
normal cells into tumour cells. p53 is a stress-response protein, which
suppresses tumour formation by triggering programmed cell death (apoptosis);
by activating cell-cycle
checkpoints that prevent damaged cells from proliferating; or by
promoting senescence
(permanent cell-cycle arrest). Thus, inactivation of p53 facilitates
the expansion of aberrant cells and leads to rampant genome instability.
Five papers (1–5) published online in Nature describe
how disruption of the p53 network also enhances the production of induced
pluripotent stem (iPS) cells. Although these observations catapult
p53 into the centre of stem-cell research, time will tell whether they
represent a promise or a warning.
iPS cells were first produced three years ago (6)
by the enforced expression of genes encoding four transcription factors
(c-Myc, Klf4, Sox2 and Oct4) in mouse fibroblast cells. These cells have
the same capabilities as embryonic stem (ES) cells isolated from
early mammalian embryos — they can self-renew, and are able to give rise
to all tissue types of the body. ES cells hold promise as a potential treatment
for various various diseases; and because iPS cells can be produced from
adult cells from any individual, the availability of these cells can, in
principle, solve the ethical issues associated with ES-cell use and may
also
circumvent the need for immunologically matched cell donors. Still,
despite much enthusiasm, it is not known
whether iPS cells will be an effective treatment for human diseases.
In fact, even embryo-derived ES cells have been tested in only a few settings,
and their effectiveness and safety are not well established.
Methods for producing iPS cells have so far been inefficient. They initially involved expression of the tumour-promoting oncogene c-myc, and random insertion of foreign DNA, including DNA from viruses used as vectors, into the recipient genome — techniques that could lead to cancer. Subsequently, in a flurry of activity, researchers identified ways to produce iPS cells without c-myc (7), devoid of viral integration (8), or using only proteins for reprogramming (9). Indeed, the ‘factorology’ of iPS-cell production is all the rage, reminiscent of the early days of cancer-gene discovery, when researchers raced to identify the first genes and gene combinations that could convert normal cells to an immortal, cancerous state.
The new studies1–5 add to the frenzy by decisively showing that inactivation of p53 markedly increases the efficiency of iPS-cell production. Furthermore, Kawamura et al. (3) show that p53 deficiency simplifies iPS generation by enabling production of iPS cells with only two factors, Oct4 and Sox2. Also, three groups (1–3) show that p53-deficient iPS cells can give rise to adult tissues when implanted into mouse embryos.
As p53 inactivation promotes genome instability and cancer, the risks of producing iPS cells that lack this essential tumour suppressor may outweigh its benefits. In line with this, Marion et al. (5 )reveal that p53-deficient iPS cells are genomically unstable and are not ‘fit’ enough to efficiently produce mice. And even when mice can be generated partly from iPS cells as in the work by Hong and colleagues (1), they eventually develop tumours. In addressing such safety concerns, Utikal et al. (4) demonstrate that transient, rather than permanent, inhibition of p53 also enhances reprogramming efficiency. Still, for p53-suppressed iPS cells to be used therapeutically, it must be shown that the reconstituted tissues function normally and remain tumour free. Moreover, next-generation sequencing and other genomic technologies must be used to demonstrate that these cells do not acquire deleterious mutations.
Beyond its therapeutic implications, this body of work (1–5)
presents overlapping but contrasting views of the mechanism by which p53
limits reprogramming and, in particular, is inconclusive as to whether
interaction between the p53 network and reprogramming pathways is direct
or indirect. Li et al. (2) show that the
Ink4a/Arf locus, which encodes a cell-cycle inhibitor (p16Ink4a)
and an indirect p53 activator (p19Arf), is silenced during iPS
reprogramming. They argue that this silencing occurs early in reprogramming,
implying a direct effect of the reprogramming factors on this locus. There
is, however, no consensus about the timing of
downregulation of Ink4a/Arf expression during reprogramming
(2, 4).
Other observations (3, 4) point
to an indirect interaction between reprogramming factors and p53 through
activation of a p53-mediated stress response (for instance, apoptosis or
senescence). Accordingly, three groups (1–3) provide
evidence that one key p53 effector in the process is the cell-cycle inhibitor
p21. Indeed, Gil and colleagues (10) suggest that senescence
represents the primary barrier to reprogramming. It is well
established that cells with an intact p53 network are prone to senescence
in culture (11), and perhaps this alone explains why
normal cells are more difficult to reprogram. Accordingly, Utikal et
al. (4) show that spontaneously immortalized cells
exhibiting unrestricted growth in culture, with or without obvious p53
impairment, are readily reprogrammed into iPS cells.
At face value, the results of these studies are reminiscent of work
(12), published 25 years ago, showing that loss
of p53 facilitates cellular immortalization — a state of endless self-renewal
that is one of the first steps
towards cancer. And more recently, p53 has been implicated as a
factor that limits the self-renewal capacity of certain stem cells (13,
14).
Even in the iPS field, previous work had shown that the SV40 T antigen
— an immortalizing oncogenic protein that disables p53 — or transient inhibition
of p53 using small interfering
RNAs, enhance reprogramming efficiency (15, 16).
The current studies substantially extend and expand on these findings,
and provide new platforms for more effectively studying reprogramming.
Just as the race to find new reprogramming factors is reminiscent
of the hunt for co operating oncogenes, the remarkable similarities between
the reprogramming processes and oncogenic transformation may provide insights
into cancer (Fig. 1). Indeed, both processes require
specific combinations of collaborating genes that can produce a less differentiated
cell able to proliferate and self-renew indefinitely. All four factors
initially shown to reprogram cells are overexpressed in at least some types
of tumour, and at least two of them — c-myc and Klf4 — are
established oncogenes. Now we find that p53 — a tumour suppressor whose
loss
greatly increases the efficiency of oncogene cooperation in transforming
normal cells to tumour cells (17) — affects reprogramming
similarly. Notably, a gold-standard assay for the formation of iPS cells
is in fact a tumorigenesis assay that measures their ability to form germ-cell
tumours following transplantation into mice.
Figure 1 | Overlapping mechanisms control iPS-cell and cancer-cell production.
Normal fibroblasts, which are mature, differentiated cells, can be reprogrammed into induced pluripotent stem (iPS) cells or tumour cells by a combination of defined factors.
a, The transcription factors c-Myc and Klf4 promote reprogramming
of fibroblasts into iPS cells in a
manner that conceptually parallels their roles in transformng
normal cells into tumour cells. Oct4 and Sox2, although overexpressed
in cancers, are currently thought to function specifically to promote iPS-cell
formation.
b, Conversely, the p53 tumour-suppressor protein, which can be induced
by p19Arf, directly or indirectly limits the reprogramming of
fibroblasts into iPS cells (1–5) or into transformed
cancer cells by inducing
apoptosis, or cellular senescence through its target protein, the
cell-cycle inhibitor p21. Another cell-cycle inhibitor, p16Ink4a,
also promotes cellular senescence directly to limit both processes. The
Ink4a/Arf
locus (not shown), which encodes p19Arf and p16Ink4a,
is silenced during iPS reprogramming (2, 4).
If the processes that lead to the production of iPS cells and tumours overlap, one wonders whether so-called cancer stem cells — cells capable of self-renewal that are considered essential for the propagation of some tumour types — might initially arise through a reprogramming-like mechanism. Moreover, not all of the factors required to trigger reprogramming of cells to iPS cells are necessary for their maintenance (8, 9). If cancer arises through reprogramming-like processes, then perhaps many of the oncogenes that initiate tumour formation might be dispensable for tumour progression and, hence, be poor targets for new cancer therapies. If this proves to be the case, further studies into reprogramming might eventually point towards new treatments for cancers as well.
Valery Krizhanovsky and Scott W. Lowe are in the Cold Spring Harbor
Laboratory and Howard Hughes Medical Institute, Cold Spring Harbor, New
York 11724, USA.
e-mails: krizh@cshl.edu;
lowe@cshl.edu
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Krizhanovsky V, Lowe SW.
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47: "Bridging" and mechanical heart valves: perils, promises, and
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Goldhaber SZ.
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48: Loss of p53 induces changes in the behavior of subventricular
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Gil-Perotin S, Marin-Husstege M, Li J, Soriano-Navarro M, Zindy
F, Roussel MF, Garcia-Verdugo JM, Casaccia-Bonnefil P.
J Neurosci. 2006 Jan 25;26(4):1107-16.
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49: p53 suppresses the self-renewal of adult neural stem cells.
Meletis K, Wirta V, Hede SM, Nistér M, Lundeberg J, Frisén
J.
Development. 2006 Jan;133(2):363-9.
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50: Restoration of p53 function for selective Fas-mediated apoptosis
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peptide.
Senatus PB, Li Y, Mandigo C, Nichols G, Moise G, Mao Y, Brown MD,
Anderson RC, Parsa AT, Brandt-Rauf PW, Bruce JN, Fine RL.
Mol Cancer Ther. 2006 Jan;5(1):20-8.
PMID: 16432159 [PubMed - indexed for MEDLINE]
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51: Promises and perils of public deliberation: contrasting two
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Cohen CB.
Kennedy Inst Ethics J. 2005 Sep;15(3):269-88.
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52: Mesenchymal stem cells for myocardial infarction: promises and
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Wollert KC, Drexler H.
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53: p53-dependent gene profiling for reactive oxygen species after
benzene inhalation: special reference to genes associated with cell cycle
regulation.
Hirabayashi Y.
Chem Biol Interact. 2005 May 30;153-154:165-70. Epub 2005 Apr 22. Review.
PMID: 15935813 [PubMed - indexed for MEDLINE]
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54: Icariin-mediated modulation of cell cycle and p53 during cardiomyocyte
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Zhu D, Qu L, Zhang X, Lou Y.
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55: Of lotteries lost and partnerships forged: the perils and promises
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Trotter G.
Camb Q Healthc Ethics. 2005 Spring;14(2):131-9. No abstract available.
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56: Colonization of adjacent stem cell compartments by mutant keratinocytes.
Brash DE, Zhang W, Grossman D, Takeuchi S.
Semin Cancer Biol. 2005 Apr;15(2):97-102. Review.
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57: A new role for p53 in maintaining genetic stability in embryonic
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Xu Y.
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58: Ectopic mTERT expression in mouse embryonic stem cells does
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Lee MK, Hande MP, Sabapathy K.
J Cell Sci. 2005 Feb 15;118(Pt 4):819-29. Epub 2005 Feb 1.
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59: p53 induces differentiation of mouse embryonic stem cells by
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Lin T, Chao C, Saito S, Mazur SJ, Murphy ME, Appella E, Xu Y.
Nat Cell Biol. 2005 Feb;7(2):165-71. Epub 2004 Dec 26.
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60: Monitoring the effect of gene silencing by RNA interference
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Gimeno R, Weijer K, Voordouw A, Uittenbogaart CH, Legrand N, Alves
NL, Wijnands E, Blom B, Spits H.
Blood. 2004 Dec 15;104(13):3886-93. Epub 2004 Aug 19.
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61: High frequency electromagnetic fields (GSM signals) affect gene
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Czyz J, Guan K, Zeng Q, Nikolova T, Meister A, Schönborn F,
Schuderer J, Kuster N, Wobus AM.
Bioelectromagnetics. 2004 May;25(4):296-307.
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62: Stem cell research: the facts, the myths and the promises.
Lo KC, Chuang WW, Lamb DJ.
J Urol. 2003 Dec;170(6 Pt 1):2453-8. Review.
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63: When is a stem cell really a stem cell?
Spangrude GJ.
Bone Marrow Transplant. 2003 Aug;32 Suppl 1:S7-11. Review.
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64: Elevated expression of exogenous Rad51 leads to identical increases
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Domínguez-Bendala J, Priddle H, Clarke A, McWhir J.
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65: Enhanced recovery of radiation-induced translocations from spermatogonial
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van Buul PP, van Duijn-Goedhart A.
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66: Ets1 is required for p53 transcriptional activity in UV-induced
apoptosis in embryonic stem cells.
Xu D, Wilson TJ, Chan D, De Luca E, Zhou J, Hertzog PJ, Kola I.
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67: Serial transplantation of p53-deficient hemopoietic progenitor
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Hirabayashi Y, Matsuda M, Aizawa S, Kodama Y, Kanno J, Inoue T.
Exp Biol Med (Maywood). 2002 Jul;227(7):474-9.
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68: p53 mutation in breast cancer. Correlation with cell kinetics
and cell of origin.
Megha T, Ferrari F, Benvenuto A, Bellan C, Lalinga AV, Lazzi S,
Bartolommei S, Cevenini G, Leoncini L, Tosi P.
J Clin Pathol. 2002 Jun;55(6):461-6.
PMID: 12037031 [PubMed - indexed for MEDLINE]
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69: Targeted point mutations of p53 lead to dominant-negative inhibition
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de Vries A, Flores ER, Miranda B, Hsieh HM, van Oostrom CT, Sage
J, Jacks T.
Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2948-53. Epub 2002 Feb 26.
PMID: 11867759 [PubMed - indexed for MEDLINE]
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70: Generation and characterization of p53 null transformed hepatic
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Dumble ML, Croager EJ, Yeoh GC, Quail EA.
Carcinogenesis. 2002 Mar;23(3):435-45.
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71: All-trans-retinoic acid-mediated modulation of p53 during neural
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Sarkar SA, Sharma RP.
Cell Biol Toxicol. 2002;18(4):243-57.
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Hirai M, LaFace D, Robinson S, Kelsey L, Johnson R, Wen SF, Warkentin
P, Mills K, Vaillancourt M, Chavez J, Leutzinger C, Sumegi J, Neugebauer
S, Lehman J, Talmadge C, Maneval D, Talmadge J.
Cancer Gene Ther. 2001 Dec;8(12):936-47.
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73: Stem cells: the promises and pitfalls.
Nowakowski RS, Hayes NL.
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74: BRCA1 is a selective co-activator of 14-3-3 sigma gene transcription
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Aprelikova O, Pace AJ, Fang B, Koller BH, Liu ET.
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75: Hepatoblast-like cells populate the adult p53 knockout mouse
liver: evidence for a hyperproliferative maturation-arrested stem cell
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Dumble ML, Knight B, Quail EA, Yeoh GC.
Cell Growth Differ. 2001 May;12(5):223-31.
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76: Role of cell cycle control in radiosensitization of mouse spermatogonial
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Van Buul PP, Van Duyn-Goedhart A, Beumer T, Bootsma AL.
Int J Radiat Biol. 2001 Mar;77(3):357-63.
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77: Adenovirus-mediated delivery of p53 results in substantial apoptosis
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Liu Q, Gazitt Y.
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78: Switch from p53 to MDM2 as differentiating human keratinocytes
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Dazard JE, Piette J, Basset-Seguin N, Blanchard JM, Gandarillas
A.
Oncogene. 2000 Aug 3;19(33):3693-705.
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79: Dissecting complex genetic diseases: promises and perils.
Tay AH, Yap HK.
Ann Acad Med Singapore. 2000 May;29(3):277. No abstract available.
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80: Cybermedicine: promises and perils.
Passi GR.
Indian Pediatr. 2000 May;37(5):481-5. No abstract available.
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81: Purging of human breast cancer cells from stem cell products
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Hirai M, Kelsey LS, Vaillancourt M, Maneval DC, Watanabe T, Talmadge
JE.
Cancer Gene Ther. 2000 Feb;7(2):197-206.
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82: NMDA receptor mediated Ca2+ responses in neurons differentiated
from p53-/- immortalized Murine neural stem cells.
Yamada K, Hisatsune T, Uchino S, Nakamura T, Kudo Y, Kaminogawa
S.
Neurosci Lett. 1999 Apr 2;264(1-3):165-7.
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83: P53-dependent and -independent links between DNA-damage, apoptosis
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Corbet SW, Clarke AR, Gledhill S, Wyllie AH.
Oncogene. 1999 Feb 25;18(8):1537-44.
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84: Adenovirus p53 purging for human breast cancer stem cell products.
Hirai M, Kelsey LS, Maneval DC, Vaillancourt M, Talmadge JE.
Acta Haematol. 1999;101(2):97-105.
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85: Strand asymmetry of CpG transitions as indicator of G1 phase-dependent
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Rodin SN, Rodin AS.
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86: Absence of p53-dependent cell cycle regulation in pluripotent
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Schmidt-Kastner PK, Jardine K, Cormier M, McBurney MW.
Oncogene. 1998 Jun 11;16(23):3003-11.
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87: p53-independent DNA repair and cell cycle arrest in embryonic
stem cells.
Prost S, Bellamy CO, Clarke AR, Wyllie AH, Harrison DJ.
FEBS Lett. 1998 Apr 3;425(3):499-504.
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88: Resistance of differentiating spermatogonia to radiation-induced
apoptosis and loss in p53-deficient mice.
Hasegawa M, Zhang Y, Niibe H, Terry NH, Meistrich ML.
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89: ES cells do not activate p53-dependent stress responses and
undergo p53-independent apoptosis in response to DNA damage.
Aladjem MI, Spike BT, Rodewald LW, Hope TJ, Klemm M, Jaenisch R,
Wahl GM.
Curr Biol. 1998 Jan 29;8(3):145-55.
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90: The p53-deficient hemopoietic stem cells: their resistance to
radiation-apoptosis, but lasted transiently.
Hirabayashi Y, Matsuda M, Matumura T, Mitsui H, Sasaki H, Tukada
T, Aizawa S, Yoshida K, Inoue T.
Leukemia. 1997 Apr;11 Suppl 3:489-92.
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91: Comparative alterations in p53 expression and apoptosis in the
irradiated rat small and large intestine.
Arai T, Kida Y, Harmon BV, Gobé GC.
Br J Cancer. 1996 Aug;74(3):406-12.
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92: Selective elimination (purging) of contaminating malignant cells
from hematopoietic stem cell autografts using recombinant adenovirus.
Wroblewski JM, Lay LT, Van Zant G, Phillips G, Seth P, Curiel D,
Meeker TC.
Cancer Gene Ther. 1996 Jul-Aug;3(4):257-64.
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93: Simian virus 40 T antigen-induced amplification of pre-parietal
cells in transgenic mice. Effects on other gastric epithelial cell lineages
and evidence for a p53-independent apoptotic mechanism that operates in
a committed progenitor.
Li Q, Karam SM, Gordon JI.
J Biol Chem. 1995 Jun 30;270(26):15777-88.
PMID: 7797580 [PubMed - indexed for MEDLINE]
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94: Expression of the wild-type p53 antioncogene induces guanine
nucleotide-dependent stem cell division kinetics.
Sherley JL, Stadler PB, Johnson DR.
Proc Natl Acad Sci U S A. 1995 Jan 3;92(1):136-40.
PMID: 7816803 [PubMed - indexed for MEDLINE]
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95: p53 expression in cultured cells following radioisotope labelling.
Dover R, Jayaram Y, Patel K, Chinery R.
J Cell Sci. 1994 May;107 ( Pt 5):1181-4.
PMID: 7929627 [PubMed - indexed for MEDLINE]
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96: Promises and perils of managed competition.
Caldwell JR.
J Fla Med Assoc. 1993 Nov;80(11):735-6. No abstract available.
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97: Hematopoietic cells from mice deficient in wild-type p53 are
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Lotem J, Sachs L.
Blood. 1993 Aug 15;82(4):1092-6.
PMID: 8353276 [PubMed - indexed for MEDLINE]
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98: The promises and perils of treating the elderly hypertensive.
Kaplan NM.
Am J Med Sci. 1993 Mar;305(3):183-97. Review.
PMID: 8447339 [PubMed - indexed for MEDLINE]
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99: Blood stem cells: promises and problems.
Hardy C.
Blood Cells. 1991;17(2):310-2. Review. No abstract available.
PMID: 1680501 [PubMed - indexed for MEDLINE]
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100: Post-transcriptional control of myc and p53 expression during
differentiation of the embryonal carcinoma cell line F9.
Dony C, Kessel M, Gruss P.
Nature. 1985 Oct 17-23;317(6038):636-9.
PMID: 2414665 [PubMed - indexed for MEDLINE]
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