preventing chemo, radiation treatments from causing new cancers--progress

[Lani]

as well as progress in decreasing treatment side-effects


Discoveries about tumor-suppressing protein could help reduce cancer-treatment side effects
[Stanford School of Medicine]

Researchers at the Stanford University School of Medicine have untangled two distinct ways in which a common, naturally occurring "tumor-suppressor" protein works. The separation of these two functions — which can have quite different consequences — could enhance efforts to develop treatment approaches that mitigate the sometimes-devastating side effects of radiotherapy and chemotherapy.

The protein, p53, is mutated or missing in more than half of all human cancers, and most cancers involve at least some compromise in its function.

Cancer is caused by two categories of mutations: those that activate oncogenes, whose protein products drive cells into overzealous replication, and those that disable tumor-suppressor genes, which code for proteins that sense this abnormal behavior and put the brakes on it.

"We knew that p53 responds to two different types of signals: DNA damage and oncogene activity," said Laura Attardi, PhD, associate professor of radiation oncology and of genetics. "We wanted to know if p53 responds to both in the same way." Attardi is senior author of a study published May 13 in Cell that throws light on crucial molecular details about how p53 works.

It is widely understood that p53 can temporarily or permanently shut down cell division in response to either acute damage to a cell's DNA or biochemical signals within a cell that suggest it's prone to becoming a cancer cell. In extreme cases, p53 convincingly counsels the cell to commit suicide, thereby preventing the possibility of a tumor arising.

Attardi and her colleagues created bioengineered mice in which various parts of p53 were incapacitated. This allowed them to determine which genes are activated by different parts of the protein, and to show that p53's aggressive DNA-damage response and its gentler tumor-suppression response are separable functions.

"We've determined, for the first time, that the gene expression program p53 requires in its tumor-suppression role is distinct from that which it requires in the context of acute DNA damage," Attardi said. "Separating these responses may allow the identification of ways to inhibit the detrimental effects of radiotherapy and chemotherapy — both of which damage DNA —without putting a patient at risk for developing new tumors."


ABSTRACT: Distinct p53 Transcriptional Programs Dictate Acute DNA-Damage Responses and Tumor Suppression
[Cell]

The molecular basis for p53-mediated tumor suppression remains unclear. Here, to elucidate mechanisms of p53 tumor suppression, we use knockin mice expressing an allelic series of p53 transcriptional activation mutants. Microarray analysis reveals that one mutant, p5325,26, is severely compromised for transactivation of most p53 target genes, and, moreover, p5325,26 cannot induce G1-arrest or apoptosis in response to acute DNA damage. Surprisingly, p5325,26 retains robust activity in senescence and tumor suppression, indicating that efficient transactivation of the majority of known p53 targets is dispensable for these pathways. In contrast, the transactivation-dead p5325,26,53,54 mutant cannot induce senescence or inhibit tumorigenesis, like p53 nullizygosity. Thus, p53 transactivation is essential for tumor suppression but, intriguingly, in association with a small set of novel p53 target genes. Together, our studies distinguish the p53 transcriptional programs involved in acute DNA-damage responses and tumor suppression—a critical goal for designing therapeutics that block p53-dependent side effects of chemotherapy without compromising p53 tumor suppression.