Monthly Archives: July 2015

Frederick Li, p53, and the Li-Fraumeni syndrome

Frederick Li passed away on June 12 of this year. In 1969, Li and Joseph Fraumeni, working together at the U.S. National Cancer Institute, discovered a familial (inherited) cancer syndrome, known as the Li-Fraumeni syndrome. Members of Li-Fraumeni syndrome families have a greatly increased risk of developing several types of cancer; particularly breast cancer, but also brain tumors, leukemias, and other cancers as well (1).

Frederick Li and Joseph Fraumeni  in 1991

In 1990, Li and Fraumeni, in collaboration with Stephen Friend and coworkers at the Massachusetts General Hospital Cancer Center, discovered that all Li-Fraumeni syndrome families harbor germ line mutations in TP53; the gene which encodes the cellular p53 protein (2). This report was the first to document that a mutation in TP53 can be inherited. What’s more, the 1990 paper proved to a previously skeptical medical community that heredity can play a major role in some cancers. [Fraumeni says that environmental factors such as air pollution, occupational exposures, diet, and even viruses were, at the time, considered far more likely causes of cancer than genetic mutation (3).]

Although Li’s research focus concerned genetic mutations that might cause cancer, rather than virology, his story is relevant to the blog because p53 is a key factor in the life cycles of the DNA tumor viruses (i.e., the polyomaviruses, papillomaviruses, and adenoviruses). Moreover, p53 was discovered by virologists. So, we begin with a brief review of the discovery of p53 and its mode of action.

In 1979, the p53 protein was discovered independently by several research groups. The discovery happened when David Lane and Lionel Crawford at the Imperial Cancer Research Fund, and Daniel Linzer and Arnold Levine at Princeton University, unexpectedly discovered a non-viral protein of molecular mass around 53 in association with immunoprecipitates of the SV40 LT protein in SV40-transformed cells.

Importantly, the SV40 LT protein was already known to be a key factor in the ability of that virus to induce neoplastic transformation. What’s more, the papillomavirus E6 gene product likewise interacts with p53, as do the adenovirus E1B proteins. Furthermore, each of these viral proteins promotes transformation, and each does so by either inactivating p53 or by facilitating its degradation. Taken together, these facts strongly implied a role for p53 in transformation. See Aside 1.

[Aside 1: Our last posting featured Harald zur Hausen and his discovery that cervical cancer is caused by papillomaviruses (4). Recall that papillomavirus genomes are integrated into the cellular DNA of cervical cancer cells. Harald zur Hausen and coworkers found that while these integrated viral genomes often contain deletions, two papillomavirus genes, E6 and E7, are present and transcribed in all cervical cancer cells; a finding which implied that these viral genes act to initiate and maintain the neoplastic state. And especially germane to the current tale, Peter Howley and coworkers demonstrated that the interaction of the papillomavirus E6 gene product with p53 results in the degradation of p53.]

At the time TP53 was discovered, it was thought to act like the oncogenes carried by the retroviral RNA tumor viruses. Retrovirus oncogenes are actually captured cellular genes, which promote cancer when they are inappropriately expressed under control of viral promoter elements. However, clues eventually emerged which pointed to a very different understanding of p53’s function. The p53 protein is actually a tumor suppressor. Evidence in that regard included the mid 1980s findings of David Wolf and Varda Rotter at the Weizmann Institute, and others as well, who showed that cell lines derived from a number of sporadic (nonfamilial) cancers have TP53 genes that are dysfunctional by mutation. Importantly, it is the loss of p53 function, rather than its expression, which may lead to cancer. [Retroviral oncogenes act dominantly when introduced into non-malignant cells, whereas mutations in tumor suppressor genes are recessive to their wild-type alleles.]

Why, we ask, do the polyomaviruses, papillomaviruses, and adenoviruses inactivate p53? The answer reveals a key tumor suppressor function of p53. Basically, it is because these DNA viruses require the cellular DNA replication enzymes and substrates to support their own DNA replication. Since these cellular enzymes and substrates are available only in dividing cells, these viruses induce cells to bypass the complex circuits that regulate exit from the G0 or “resting” phase of the cell cycle. They do this by freeing the cellular E2F transcription factor from the blocking activities of the pRb family of tumor suppressor proteins, in that way enabling cells to enter into S phase. [The multifunctional SV40 LT protein, the papillomavirus E7 gene product, and the adenovirus E1A protein carry out this function for their respective viruses.] However, p53 remains as a crucial component of a cellular surveillance mechanism that prevents cells from undergoing unscheduled and potentially disastrous cell divisions. If the cell should enter an inappropriate S phase, p53 triggers apoptosis; a cell death program that can be activated by a variety of signals from within and outside the cell. [From the point of view of the host, cell suicide by p53-mediated apoptosis is preferable to the generation of rampant daughter cells that might produce full-blown tumors.] Consequently, the clever DNA tumor viruses (which comprise three unrelated virus families) undermine the normal regulatory functions of p53, as well as those of pRb. See reference 5 for details on these mechanisms.

Li, Fraumeni, and collaborator, Stephen Friend knew that they could not identify the genetic mutation underlying the Li-Fraumeni syndrome by conventional linkage analysis. That was so because Li-Fraumeni syndrome families are quite rare and, moreover, the cancer death rate among affected family members is high (nearly all individuals who carry the mutation develop cancer). So, their strategy was to investigate plausible candidate genes. They chose TP53 because, in their words: “Inactivating mutations of p53 have been associated with sporadic osteosarcomas, soft tissue sarcomas, brain tumors, leukemias, and carcinomas of the lung and breast. Together, these tumors also account for more than half of the cancers in selected series of LFS families (2).” Furthermore, evidence was emerging that TP53 actually encodes a tumor suppressor protein.

The finding by Li, Fraumeni, Friend, and their coworkers, that the TP53 mutation is present in the normal cells of Li-Fraumeni syndrome individuals, as well as in their tumor cells, proved that the mutation is passed down through the germ line. Yet these findings raise the following interesting question. If the TP53 mutation is present in all cells of an affected individual, why does that individual have “only” one or a few tumors? The reason, at least in part, is that progression to full blown cancer requires additional genetic changes. [Apropos that, Li helped discover that people with the Li-Fraumeni syndrome are particularly prone to developing additional tumors when given radiation therapy to treat their cancers.]

Li and his collaborators closed their 1990 paper as follows: “In conclusion, we have shown that alterations of the p53 gene occur not only as somatic mutations in human cancers, but also as germ line mutations in some cancer-prone families (3).” With that paper, the three researchers, and their collaborators, became the first to demonstrate a genetic condition in which a predisposition to cancer is passed from one generation to the next.

Li was born in Canton, China, in 1940. His father was a general in the Chinese Army (Kuomintang), who fought against the Japanese domination of China during the Second World War. The Li family immigrated to the United States in 1947, and opened a Chinese restaurant in White Plains, N.Y.

At 16 years of age, Li matriculated at NYU, where he majored in physics. He earned his MD from the University of Rochester.

Li joined the NCI in 1967, but spent the last 30 years of his career at the Dana-Farber Cancer Institute in Boston, where he also held appointments as a professor at Harvard Medical School and at Harvard’s School of Public Health. In 1991, he was appointed head of Dana-Farber’s Division of Cancer Epidemiology and Control. David G. Nathan, a former president of Dana-Farber, said that Li had been recruited to Dana-Farber to bring more scientific rigor to cancer research there (3). In 1996, Li was appointed to the NCI’s National Cancer Advisory Board by President Bill Clinton.

Li founded a clinic for immigrants in Boston’s Chinatown, where he frequently treated patients at night for free. He retired from his medical activities in 2008 because of dementia resulting from Alzheimer’s disease.

In July 2012, Joseph Fraumeni celebrated his 50th anniversary as a scientist at the NCI. He observed the occasion by stepping down as the NCI’s Director of the Division of Cancer Epidemiology & Genetics. He continues to serve as a senior investigator and adviser at the NCI and NIH, where his major research contributions concerned the environmental and genetic determinants of cancer. Fraumeni is an elected member of the US National Academy of Sciences.

Stephen Friend was on the Harvard Medical School faculty from 1987 until 1995, when he joined the Fred Hutchinson Cancer Research Center as chairman of Pharmacology. His research focused on genomic analysis of large patterns of gene expression. In 1997, Friend and Leroy Hood co-founded the company, Rosetta Inpharmatics, which specialized in genomic approaches to drug discovery. When Rosetta was acquired by Merck in 2001, Friend served as a Merck Senior Vice President and led the parent company’s Oncology Early Discovery and Development Divisions. Friend left Merck in 2009 to advocate for and promote open access biomedical research. Earlier, in 1986, Friend cloned the gene encoding pRB; the first tumor suppressor gene to be isolated.


1. Li, F.P., and Fraumeni J.F. Jr. 1969. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Annals of Internal Mededicine. 71:747-752.

2. Malkin, D., F.P. Li, L.C. Strong, J.F. Fraumeni Jr, C.E. Nelson, D.H. Kim, J. Kassel, M.A. Gryka, F.Z. Bischoff, M.A. Tainsky, and S.H. Friend. 1990. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233-1238.

3. Grady, D., Frederick P. Li, Who Proved a Genetic Cancer Link, Dies at 75, N.Y. Times, June 21, 2015.

4. Harald zur Hausen, Papillomaviruses, and Cervical Cancer, Posted on the blog June 19, 2015.

5. Norkin, L.C. 2010. Virology: Molecular Biology and Pathogenesis, ASM Press.