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    LDP1 Directly Links the Tumor Suppressor Protein P53 to Iron Metabolism

    Scientific Abstract:
    Background The tumor suppressor protein p53 induces cell cycle arrest and/or apoptosis in response to cellular stresses. p53 exerts its effects mainly as a transcription factor, but has additional mechanisms of action. Half of human cancers carry p53 gene mutations. However, breast cancers show a significantly lower frequency of p53 mutations, suggesting that breast cancers often inactivate the p53 pathway by other means. To identify novel negative-regulatory proteins of p53, a genetic screen was performed using a yeast p53 assay. Besides known p53 inhibitors, the screen identified a protein central to iron metabolism, termed LDP1 (for L. Dearth protein 1), that physically interacts with p53. Abnormalities of iron metabolism correlate with more aggressive breast cancers, and manipulation of iron metabolism, such as, for example, through iron chelators, inhibits growth and induces apoptosis of breast cancer cell lines. However, iron metabolism and p53 have thus far not been directly linked. Objective/Hypothesis We propose that the activities of p53 are directly affected by the iron metabolism. We hypothesize that LDP1 represents this direct link and that high levels of LDP1, as found in breast cancers, inhibit p53. The objective of this proposal is to characterize the interaction of p53 with LDP1 and to define the effects of LDP1 on p53 activities. Specific Aims (1) Characterize the interaction of p53 with LDP1, a central protein of iron metabolism. (2) Determine the effects of LDP1 on p53 function. Study Design Experiments will rely on tissue culture based assays using established breast cancer cell lines. The interaction of LDP1 with p53 will be studied mainly by co-immunoprecipitation assays in mammalian cells using deletion constructs for p53 and LDP1. Studies of the effect of LDP1 on p53 function will incorporate the use of iron chelators and siRNA technology. Potential Outcomes and Benefits of the Research It is known that tumor cells have higher levels of iron, which is required for increased proliferation, as compared to normal cells. Therefore, iron chelators have been explored as potential cancer therapies. The proposed work focuses on establishing a direct link between iron metabolism and p53 inhibition. Studies of LDP1 may define a new mechanism of p53 inactivation in breast cancers. This knowledge may result in new strategies to exploit the abnormal iron metabolism of breast cancer cells.

    Lay Abstract:
    The p53 protein is important for protecting humans from breast cancer. It responds to various types of cellular stress and either stops the cell from dividing or induces programmed cell death. p53 is a transcription factor that activates downstream genes, but it has additional mechanisms of action that mediate its effects. The p53 gene is mutated in half of all human cancers, but in breast cancers the frequency of such mutations is much lower. This suggests that breast cancers use other means to rid themselves of p53 activity. It is well established that breast cancers have an abnormal iron metabolism. Iron is important for many cellular functions, such as cell division. Breast cancers often have increased levels of iron and increased levels of proteins that are important for the storage and metabolism of iron. Numerous studies have shown that manipulation of iron metabolism affects breast cancer cells. For example, chemicals called iron chelators sequester iron and, by reducing iron levels in breast cancer cells, cause growth arrest or even death. Experimental strategies to remove proteins important for iron metabolism have resulted in similar outcomes. Clinical studies suggest that high levels of proteins important for iron metabolism identify more aggressive breast cancers. Thus far, the fundamental process of iron utilization by breast cancer cells and the tumor suppressor protein p53 have not been linked. Using a large yeast-based genetic screen, we have identified one central protein of iron metabolism (termed LDP1 for L. Dearth protein 1) that physically interacts with p53. We think that LDP1 is key to understanding how the activities of p53 are linked to iron metabolism. We propose that abnormally high levels of LDP1 that are found in breast cancers cause inactivation of p53. This p53 inactivation then contributes to the development of aggressive breast cancers. We will study the interaction of p53 with LDP1. And we will determine whether and how LDP1 inhibits p53. We will also use several techniques, including iron chelators, to determine whether we can reactivate p53 in breast cancer cells by removing the activity of LDP1. Tumor cells are known to have higher levels of iron. Our studies will evaluate the intriguing possibility that p53 activities in breast cancer cells are inhibited because of high levels of LDP1. Our work thus may define a new mechanism of p53 inactivation. Once established, this knowledge will lead to new therapeutic strategies to affect the growth of breast cancers by exploiting their abnormalities in iron metabolism.