The first 30 years of p53.docx

1、The first 30 years of p53The first 30 years of p53: growing ever more complexArnold J. Levine1 and Moshe Oren21Institute for Advanced Study, Princeton, NJ2Weizmann Institute of Science, Rehovot, IsraelThe publishers final edited version of this article is available at Nat Rev CancerSee other article

2、s in PMC that cite the published article. Other Sections o Abstracto Prelude: tumor viruses, oncogenes and the road to p53o The early years: p53 is an oncogene?o Grand entry into the tumor suppressor main stageo How does p53 do it?o p53 and MDM2: in and out of loopso What is this good for? p53 and c

3、ancer therapyo Restoring p53 activityo The Futureo ReferencesAbstractThirty years ago, p53 was discovered as a cellular partner of SV40 Large Tumor Antigen, the oncoprotein of this tumor virus. The first decade of p53 research saw the cloning of p53 DNA and the realization that p53 is not an oncogen

4、e but a tumor suppressor that is very frequently mutated in human cancer. In the second decade, the function of p53, a transcription factor induced by stress, resulting in cell cycle arrest, apoptosis and senescence, was uncovered. In its third decade new functions were revealed, including regulatio

5、n of metabolic pathways and cytokines required for embryo implantation. The fourth decade may see new p53-based drugs to treat cancer. What is next is anybodys guess. Other Sections o Abstracto Prelude: tumor viruses, oncogenes and the road to p53o The early years: p53 is an oncogene?o Grand entry i

6、nto the tumor suppressor main stageo How does p53 do it?o p53 and MDM2: in and out of loopso What is this good for? p53 and cancer therapyo Restoring p53 activityo The Futureo ReferencesBy now, anybody with interest in cancer research is already well aware of the existence of p53 and its relevance t

7、o practically every aspect of tumor biology 1. It is impossible to overlook the prominence of p53: with nearly 50,000 PubMed-listed publications so far and a steady flow of new ones hitting the cyberspace every week, p53 is undoubtedly one of the most extensively studied genes and proteins. Every ot

8、her year hundreds of scientists gather for an International p53 Workshop to discuss a single gene and protein. However, the notion that p53 is a pivotal tumor suppressor and a major mainstay in our bodys natural anti-cancer defense, now taken for granted, did not come easily. When discovered 30 year

9、s ago, p53 was little more than just another “interesting” protein that most cancer researchers did not consider worthy of much attention, let alone of investment of research time and resources. Unlike well-behaved oncogenes, which were often brought into the main stage shortly after their discovery

10、, p53 received relatively little attention in its first years. The road leading to p53s eventual rise to prominence and its recognition as the most frequently altered gene in human cancer was rather long and winding, with concepts being repeatedly revised, extensively modified and sometimes even tot

11、ally turned upside down. The history of p53 research over the last 30 years provides a rich example of how knowledge evolves in unexpected ways and how both research “fashions” and new methodological breakthroughs make us perceive the same facts in totally different ways as time progresses. It also

12、teaches us how extensive delving into a single protein can lead to the discovery of new fundamental and general principles that apply to much broader areas of biology and biochemistry. Other Sections o Abstracto Prelude: tumor viruses, oncogenes and the road to p53o The early years: p53 is an oncoge

13、ne?o Grand entry into the tumor suppressor main stageo How does p53 do it?o p53 and MDM2: in and out of loopso What is this good for? p53 and cancer therapyo Restoring p53 activityo The Futureo ReferencesPrelude: tumor viruses, oncogenes and the road to p53In the 1970s, much of the attention of “mod

14、ern” cancer researchers focused on cancer-causing viruses. In particular, it became evident that such viruses carried oncogenes. The bigger picture was first resolved for RNA tumor viruses; there, it was shown that the virus “hijacks” a cellular gene, which it subsequently reintroduces into the cell

15、 that it infects 2. This leads to the vast overexpression of the encoded cellular protein, sometimes in modified form, and eventually causes transformation. Similarly, oncogenes were uncovered by examining the genes adjacent to the integration sites of retroviruses that resulted in the overexpressio

16、n of those genes and the formation of tumors in animals.Over the next fifteen years a long list of oncogenes were identified and it became clear that oncogenes were the cause of cancers in animals. It was thus not at all far-fetched to expect that DNA tumor viruses might operate by essentially the s

17、ame principle that they had picked up oncogenes from the cell or encoded their own viral oncogenes. It became rapidly clear that the DNA tumor viruses contained oncogenes not related to the cellular oncogenes of the RNA tumor viruses. But how did these viral oncogenes act to transform cells and prod

18、uce tumors in animals? It was proposed that the DNA tumor virus oncogenes encode viral proteins that lead indirectly to the excessive induction of putative cellular oncoproteins. It was on that fertile conceptual soil that p53 first emerged.Tumors induced in experimental animals by small DNA tumor v

19、iruses, such as SV40, typically express a limited number of viral encoded proteins. These are recognized by the immune system of the host, leading to the production of antibodies against these proteins. By the mid-1970s, such antibodies started to gain popularity as tools to identify and monitor pro

20、teins encoded by the viral genome and expressed in transformed cells. Based on their mode of detection, these proteins were dubbed viral tumor antigens. Subsequent genetic analysis revealed that the genes encoding these viral tumor antigens were often those also responsible for the transforming acti

21、vity of the virus, namely the viral oncoproteins. In the case of SV40, the two viral proteins identified in this manner were called large T-antigen and small t-antigen, respectively.It was while studying these SV40-derived tumor antigens that several groups independently stumbled on p53. This happen

22、ed in 1979, thirty years ago (Timeline). Working at the ICRF (now London Institute for Cancer Research), David Lane and Lionel Crawford realized that when sera from animals bearing SV40-induced tumors were employed to immunoprecipitate SV40 large T-antigen, a non-viral protein with an apparent molec

23、ular mass of about 53 kDa came along for the ride 3. Further analysis established that this cellular protein was physically complexed with SV40 large T-antigen. Thus the viral protein, previously shown to be largely responsible for the transforming and tumorigenic activity of the SV40 virus, had sel

24、ected this hitherto unknown cellular protein as its partner for an intimate, specific interaction. At the same time, Daniel Linzer and Arnold Levine applied a similar immunological approach to SV40 transformed cells, and came up with essentially the same observations, namely that such cells harbored

25、 a complex between the SV40 large T-antigen and the cellular 53 kDa protein 4. Three other groups, those of Alan Smith in the UK, Robert Carroll in New York and Pierre May in France, simultaneously made very similar findings, all published in 1979 5-7.Interestingly, Linzer and Levine also found that

26、 their antisera precipitated the same 53 kDa protein from teratocarcinoma (a germ cell tumor)-derived cells, despite the fact that the latter did not harbor any SV40 proteins; this indicated that a subset of the antibodies raised against the viral-induced tumor were capable of interacting directly w

27、ith this cellular protein 4. In parallel, Lloyd Old and coworkers demonstrated that animals immunized with non-virally transformed cells produced antibodies to the same 53 kDa protein 8, rightfully qualifying it as a cellular tumor antigen. Moreover, Varda Rotter, working in the lab of David Baltimo

28、re, was able to identify the same protein being produced in excess in cells transformed by a retrovirus, the Abelson murine leukemia virus 9. Hence, very high levels of this new cellular protein were present not only in SV40-transformed cells but also in other types of cancer cells, but little or no

29、 p53 protein could be detected in non-transformed cells.As is often the case with independent discoveries of the same protein, each lab gave it a different name and continued to publish subsequent papers using their favorite name, creating quite a bit of confusion in this very young field. It was on

30、ly in 1983, during the first p53 Workshop in Oxted, UK (Fig. 1), that representatives of the different p53 groups got together to discuss a common nomenclature. After a reasonable deal of inevitable debate, the term “p53” emerged as the winner and has stayed with us ever since. Ironically, p53 is ac

31、tually a misnomer. When coined, it purportedly related to the molecular mass of the protein, which on the basis of its migration in SDS-polyacrylamide gels was estimated to be about 53 kDa. As realized later, this was a gross overestimate, presumably due to the presence of a proline-rich region that

32、 slows down the migration of the protein in such gels. In fact, the correct molecular mass of the human p53 protein is only 43.7 kDa, and that of the mouse protein is even less. But who would dare change a winning name?Fig. 1 The first p53 workshopFig. 1The first p53 workshopThe first p53 workshop took place at The Marie Curie Research Institute at The Chart in Oxted, Surrey, UK from 7-10 May 1983. The program did not include any presentation titles, but the hottest issued on the agenda were the first disclosures of the cloned murine p53 cD