MOLECULAR MECHANISM OF NDP KINASE A IN TUMOR METASTASIS

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The long-term goal of this project is to understand how human NDP kinase A (NDPK-A) is involved in tumor metastasis, a major cause of death in cancer patients. An increased NDPK-A level is strongly correlated with high metastatic potential of neuroblastoma. This suggests that NDPK-A may be a metastasis promoter in this cancer. In addition, we have detected the Serl20 yields Gly mutation of NDPK-A in 26 percent of patients with metastatic neuroblastoma. Although NDPK-A is known to function as a phosphate transferase and participate in nucleic acid metabolism, this enzymatic activity is not correlated with tumor metastasis, suggesting other function(s) of NDPK-A in tumor progression. In fact, our preliminary data demonstrate that NDPK-A can function as a transcription factor in vitro by binding to a cis-acting element in the c-myc gene and activating c-myc transcription. We hypothesize that NDPK-A promotes the metastasis of neuroblastoma by deregulating c-myc transcription. Five specific aims are proposed to test facets of the hypothesis in neuroblastoma cell and SCID mice model systems: (1) Examine if alterations in the protein level and structure of NDPK-A affect nuclear localization of NDPK-A. (2) Examine if alterations in the protein level and structure of NDPK-A enhance cell growth and invasiveness. (3) Determine if neuroblastoma cells expressing an altered protein level and structure of NDPK-A promote tumor formation and metastasis in SCID mice. (4) Study the deregulation of c-myc transcription by NDPK-A in vivo. (5) Elucidate the potential target genes which are regulated by NDPK-A. Findings from the proposed in-vitro and in-vivo studies will establish whether NDPK-A promotes the metastasis of neuroblastoma. The results may point to one or more specific cellular processes that are affected by alterations in the protein level and structure of NDPK-A. We will also obtain new information regarding the deregulation of c-myc transcription by NDPK-A. Furthermore, identification of the consensus sequence recognized by NDPK-A will allow the identification of its potential target genes and expand our understanding of the NDPK-A network.