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Cell and Molecular Biology Program - Cancer Biology

Graduate Program in Molecular Biosciences & Bioengineering (MBBE)

American Chemical Society

Role of polyamines in MYCN-amplified neuroblastoma
Neuroblastoma (NB) is the most common extracranial tumor of childhood with approximately 700 new cases per year in the United States. MYCN gene amplification occurs in approximately 20% of primary NB tumors, and is strongly associated with advanced stage disease, rapid tumor progression, and poor prognosis (Fig. 1)

Figure 1: Confocal laser microscope images of human NB cells
Bachmann Lab, 2001

Ornithine decarboxylase (ODC) is a key enzyme in the biosynthesis of polyamines, which have been implicated in tumor cell proliferation. Increased ODC levels and elevated polyamine titers are sustained in rapidly proliferating cells and the suppression of polyamine biosynthesis has been considered an attractive therapeutic approach for many cancers. The ODC gene is a transcriptional target of MYCN, and we speculate that the ability of this transcription factor to promote NB cell
cycle progression may be due in part to its transcriptional activation of ODC.

In this project, we seek to understand how ODC and polyamines regulate cell cycle progression, cell survival, and apoptosis. More specifically, we search for ODC/polyamine-regulated genes and proteins, which directly control these key events in NB cells. Specific proteins of interest are AKT/PKB, p27^Kip1, MYCN, retinoblastoma protein Rb, p53, Mdm2, Cdks, and associated regulatory proteins (Fig. 2)

Figure 2: Proposed interplay between polyamines and cell cycle regulatory
proteins in MYCN-amplified neuroblastoma cells

We propose the use of clinically tested polyamine inhibitors including DFMO, SAM486A, and/or polyamine analogs for the treatment of NB patients.

Role and regulation of PRAF2, a new CCR5-interacting protein
Chemokine receptors play an important role in cell migration, cancer metastasis, and HIV-1 transmission. PRAF2 is a new chemokine receptor CCR5-interacting protein. Our work has shown that PRAF2 is widely expressed in human tissues with high expression in the brain. Tumor tissues of breast, colon, ovary, and lung express exceptionally high levels of PRAF2 compared to normal tissue of the same patient. In this project, we are using molecular, biochemical, and cell biology approaches including RNA interference to better understand the location and function of PRAF2. In particular, we examine whether PRAF2 promotes CCR5 receptor-mediated endocytosis and controls endosomal Rab protein-regulated vesicle transport. We found that PRAF2 colocalizes with endosome-resident proteins (Fig. 3).

Figure 3: Colocalization of endogenous PRAF2 and
early endosome-resident protein in NB cells

Because chemokine receptors are involved in many cellular processes, our research provides new insights into the treatment of a number of diseases and medical conditions including cancer, HIV/AIDS, rheumatoid arthritis, diabetes, and male infertility/sperm chemotaxis.