Previous research has attributed p53 activation to the passive diffusion of ribosomal protein L11 from the nucleolus, the part of the nucleus where ribosomes are produced to the nucleoplasm.
The UC research, however, suggests that p53 activation is not due to nucleolar breakdown, but is actually the result of an active increase in the production of L11. They suggest that in DBA, a series of L11 interactions results in cell cycle arrest and ultimately leads to cell death and anemia.
"Previous studies suggested L11 was passively coming out of the nucleolus when ribosome production was disrupted. Our study actually showed that the nucleolus stayed intact as ribosomes were still being produced, suggesting selective upregulation of L11," explains Thomas, the John and Gladys Strauss endowed professor of cancer biology at UC and scientific director at UC's Genome Research Institute. "If we can target the L11 interaction, we might be able to spare other stress pathways that mediate potential benefits of p53 induction."
Thomas believes DBA slowly evolves into cancer when this specific molecular checkpoint is lost. This results in the body being genetically reprogrammed over time, leading to the onset of additional medical problems, particularly leukemia, in DBA patients later in life.
"By understanding the chain of biological events leading to this abnormal cell death and targeting the specific molecular checkpoint that controls cell death, we may be able to develop new drugs that would interrupt or stop the process and allow the body to recover, rebuilding healthy bone marrow," adds Thomas.
This research was funded in part by the National Cancer Institute's Mouse Models in Human Cancer Consortium. In addition to Th
|Contact: Amanda J. Harper|
University of Cincinnati