News News Researchers Gain Insights Into Suppressor Gene Function Findings presented at the Eighth Annual Meeting on Oncogenes, held recently at Hood College in Frederick, Md., revealed new insights into how the suppressor genes RB and p53 work. "We've seen a major advance in our understanding of the mechanism of both RB and p53," said Eva Lee, Ph.D., who chaired a session on tumor suppressor genes at the meeting. "A common theme seems to be that the function of p53 and RB proteins is mediated by their association with other cellular proteins." Evidence that RB and p53 are normally involved in inhibiting cell growth has been accumulating steadily for the past decade. The loss or inactivation of these genes is now hypothesized to be an important genetic change that increases the potential for cancer. However, progress in dissecting how these anti-proliferative effects come about has lagged.
via a series of messenger molecules. At the nucleus, these messengers interact with nuclear proteins that either promote or, as with p53 and RB, inhibit cell growth. Much of tumor suppressor research has focused on finding the proteins that bind to and regulate the p53 and RB protein products, presumably at the end of a signal transduction cascade. The discovery of one such protein, reported by Jamil Momand, Ph.D., and his colleagues at Princeton University and the University of Pennsylvania, is particularly important, according to Lee.
Signal Transduction "Momand has found that p53 forms a complex with the mdm-2 gene product," said Lee, who explained that mdm-2 is an oncogenic protein whose overexpression is known to promote tumor growth. One possible interpretation of this association is that the relative amounts of p53 and mdm-2 determine whether p53's suppressing effect or mdm-2's proliferative effect wins out. The real significance
Regulator Proteins "p53 and RB are nuclear proteins — that is, their protein products are localized to the cell nucleus," explained Lee, an associate professor at the University of Texas Health Science Center, Institute of Biotechnology in San Antonio. "This creates a lot of questions relating to signal transduction — how do extracellular growth factors interact with nuclear genes and gene products? This has been very mysterious." Signal transduction, said Lee, can be conceived as a cascade of events whereby the original signal, outside the cell, is transmitted across the cell membrane and ultimately to the nucleus Vol. 84, No. 16, August 19, 1992
Dr. Eva Lee
of this finding, said Lee, is that it helps elucidate the p53 tumor suppression mechanism. "What this does is suggest a link between p53 tumor suppression and signal transduction," she said. "But, at this time, mdm-2's role in signal transduction is unclear."
Similar Mechanisms The identification of an RB-binding protein, reported by Lee's group at the Institute of Biotechnology, provides a clearer connection between RB tumor suppression and signal transduction. "We have cloned a protein, p48, that is associated with RB," said Lee. "p48 seems like a good candidate for establishing the link [with signal transduction] because it is very similar to a yeast gene that is known to be induced in signal transduction." Evidence that a known growth regulator, the E2F protein, is also associated with the RB protein was also reported at the meeting. Researchers led by Ed Harlow, Ph.D., at the Massachusetts General Hospital Cancer Center in Charlestown cloned the E2F gene, whose protein product they found complexed with the RB protein. "Harlow's work provides the first conclusive evidence that the E2F protein is interacting with RB," said Lee. "It also lends further support to our working hypothesis that RB regulates cell growth by associating with a variety of cellular proteins." The similar functional mechanisms for p53 and RB suggested by the new findings contrast with other findings presented at the meeting that revealed fundamental differences between the two. Researchers from Baylor College of Medicine in Houston reported that p53deficient mice develop normally but are more susceptible to tumors than normal mice. Lee's group has done similar experiments with RB-deficient mice. "Our preliminary data suggest that, unlike p53, NEWS
1233
News News Sun-Less Tans May Be Possible With New Synthetic Hormone Imagine taking a shot or pill, or using a lotion to get a year-round tan and protection from skin cancer. Researchers at the Arizona Cancer Center and University of Arizona are testing analogues of melanotropin-stimulating hormone to develop just such a product. They call it Melano-Tan. Right now they are in phase I testing of two forms of the drug. The ultimate goal is to demonstrate that Melano-Tan is protective against skin cancer, according to Norman Levine, M.D., chief of the Dermatology Section at the University of Arizona. Dr. EdHtrtow
the RB gene product is necessary for normal fetal development," she said. Thus far, said Lee, none of the RB-deficient mice have survived until birth. Tumor suppressor genes already have been found to be useful prognostic indicators for some cancers. Sensitive screening technologies, like the polymerase chain reaction, may eventually permit the clinical diagnosis of suppressor gene mutations for a broad spectrum of cancers. The emerging insights into tumor suppressor gene function, Lee said, will have important implications for cancer treatment, leading perhaps to tumor suppressor gene therapies. She added, however, that much work remains before the basic science of the oncogene researchers can be translated into useful cancer treatments. "One of the major difficulties for gene therapies with tumor suppressor genes is the delivery system," said Lee. 'To be effective, the wild-type (normal) tumor suppressor gene would have to be introduced into every tumor cell." —John Bowersox 1234
UV Protection Melano-Tan stimulates production of melanin, which makes the skin darker. "We know we can darken folks, we want to see if it is indeed protective against sun damage," said Robert T. Dorr, PhD., director of the Cancer Pharmacology Research Program at the cancer center. The hypothesis is that increased melanin in the skin may afford protection against the effects of ultraviolet light for people who sunburn easily. The researchers tested Melano-Tan I in 1990 on 14 healthy men compared with 14 controls. Injections over a two-week period resulted in tans for people who ordinarily tan poorly as well as those who tan well. Evidence of a tan appeared at two weeks, with a peak at three to four weeks. By the seventh week, the tan began to fade. Side
effects were minimal, including vague gastrointestinal discomfort and a flushing sensation that lasted an hour after injection. Only body areas that are normally exposed to the sun became tanned. The men's trunks and buttocks did not tan. It may be that melanocytes in certain areas of the body are more amenable to stimulation by hormones, Levine said. Early pilot tests indicate that with longer drug exposure, areas that initially didn't darken, began to darken.The Arizona team is working to develop an agent that can be delivered orally, topically, or as a nasal spray, Levine said. Melano-Tan I has only tanned effectively through injections. Pills or lotions containing the compound are not absorbed well, Dorr said.
Better Absorption Another version of the drug, MelanoTan n, is a smaller compound. It contains half the amino acids of Melano-Tan I, with a smaller surface area, so absorption orally and topically is much improved, according to Dorr.
Tbt frog oo the right turned dark brown after an Injection of Melano-Tan.
Journal of the National Cancer Institute
via a series of messenger molecules. At the nucleus, these messengers interact with nuclear proteins that either promote or, as with p53 and RB, inhibit cell growth. Much of tumor suppressor research has focused on finding the proteins that bind to and regulate the p53 and RB protein products, presumably at the end of a signal transduction cascade. The discovery of one such protein, reported by Jamil Momand, Ph.D., and his colleagues at Princeton University and the University of Pennsylvania, is particularly important, according to Lee.
Signal Transduction "Momand has found that p53 forms a complex with the mdm-2 gene product," said Lee, who explained that mdm-2 is an oncogenic protein whose overexpression is known to promote tumor growth. One possible interpretation of this association is that the relative amounts of p53 and mdm-2 determine whether p53's suppressing effect or mdm-2's proliferative effect wins out. The real significance
Regulator Proteins "p53 and RB are nuclear proteins — that is, their protein products are localized to the cell nucleus," explained Lee, an associate professor at the University of Texas Health Science Center, Institute of Biotechnology in San Antonio. "This creates a lot of questions relating to signal transduction — how do extracellular growth factors interact with nuclear genes and gene products? This has been very mysterious." Signal transduction, said Lee, can be conceived as a cascade of events whereby the original signal, outside the cell, is transmitted across the cell membrane and ultimately to the nucleus Vol. 84, No. 16, August 19, 1992
Dr. Eva Lee
of this finding, said Lee, is that it helps elucidate the p53 tumor suppression mechanism. "What this does is suggest a link between p53 tumor suppression and signal transduction," she said. "But, at this time, mdm-2's role in signal transduction is unclear."
Similar Mechanisms The identification of an RB-binding protein, reported by Lee's group at the Institute of Biotechnology, provides a clearer connection between RB tumor suppression and signal transduction. "We have cloned a protein, p48, that is associated with RB," said Lee. "p48 seems like a good candidate for establishing the link [with signal transduction] because it is very similar to a yeast gene that is known to be induced in signal transduction." Evidence that a known growth regulator, the E2F protein, is also associated with the RB protein was also reported at the meeting. Researchers led by Ed Harlow, Ph.D., at the Massachusetts General Hospital Cancer Center in Charlestown cloned the E2F gene, whose protein product they found complexed with the RB protein. "Harlow's work provides the first conclusive evidence that the E2F protein is interacting with RB," said Lee. "It also lends further support to our working hypothesis that RB regulates cell growth by associating with a variety of cellular proteins." The similar functional mechanisms for p53 and RB suggested by the new findings contrast with other findings presented at the meeting that revealed fundamental differences between the two. Researchers from Baylor College of Medicine in Houston reported that p53deficient mice develop normally but are more susceptible to tumors than normal mice. Lee's group has done similar experiments with RB-deficient mice. "Our preliminary data suggest that, unlike p53, NEWS
1233
News News Sun-Less Tans May Be Possible With New Synthetic Hormone Imagine taking a shot or pill, or using a lotion to get a year-round tan and protection from skin cancer. Researchers at the Arizona Cancer Center and University of Arizona are testing analogues of melanotropin-stimulating hormone to develop just such a product. They call it Melano-Tan. Right now they are in phase I testing of two forms of the drug. The ultimate goal is to demonstrate that Melano-Tan is protective against skin cancer, according to Norman Levine, M.D., chief of the Dermatology Section at the University of Arizona. Dr. EdHtrtow
the RB gene product is necessary for normal fetal development," she said. Thus far, said Lee, none of the RB-deficient mice have survived until birth. Tumor suppressor genes already have been found to be useful prognostic indicators for some cancers. Sensitive screening technologies, like the polymerase chain reaction, may eventually permit the clinical diagnosis of suppressor gene mutations for a broad spectrum of cancers. The emerging insights into tumor suppressor gene function, Lee said, will have important implications for cancer treatment, leading perhaps to tumor suppressor gene therapies. She added, however, that much work remains before the basic science of the oncogene researchers can be translated into useful cancer treatments. "One of the major difficulties for gene therapies with tumor suppressor genes is the delivery system," said Lee. 'To be effective, the wild-type (normal) tumor suppressor gene would have to be introduced into every tumor cell." —John Bowersox 1234
UV Protection Melano-Tan stimulates production of melanin, which makes the skin darker. "We know we can darken folks, we want to see if it is indeed protective against sun damage," said Robert T. Dorr, PhD., director of the Cancer Pharmacology Research Program at the cancer center. The hypothesis is that increased melanin in the skin may afford protection against the effects of ultraviolet light for people who sunburn easily. The researchers tested Melano-Tan I in 1990 on 14 healthy men compared with 14 controls. Injections over a two-week period resulted in tans for people who ordinarily tan poorly as well as those who tan well. Evidence of a tan appeared at two weeks, with a peak at three to four weeks. By the seventh week, the tan began to fade. Side
effects were minimal, including vague gastrointestinal discomfort and a flushing sensation that lasted an hour after injection. Only body areas that are normally exposed to the sun became tanned. The men's trunks and buttocks did not tan. It may be that melanocytes in certain areas of the body are more amenable to stimulation by hormones, Levine said. Early pilot tests indicate that with longer drug exposure, areas that initially didn't darken, began to darken.The Arizona team is working to develop an agent that can be delivered orally, topically, or as a nasal spray, Levine said. Melano-Tan I has only tanned effectively through injections. Pills or lotions containing the compound are not absorbed well, Dorr said.
Better Absorption Another version of the drug, MelanoTan n, is a smaller compound. It contains half the amino acids of Melano-Tan I, with a smaller surface area, so absorption orally and topically is much improved, according to Dorr.
Tbt frog oo the right turned dark brown after an Injection of Melano-Tan.
Journal of the National Cancer Institute
