Nm23-H1 can induce cell cycle arrest and apoptosis in B cells.

Abstract

Nm23-h1 is a well-known tumor metastasis suppressor, which functions as a nucleoside-diphosphate kinase converting nucleoside diphosphates to nucleoside triphosphates with an expense of aTp. It regulates a variety of cellular activities, including proliferation, development, migration and di erentiation known to be modulated by a series of complex signaling pathway. Few studies have addressed the mechanistic action of Nm23-h1 in the context of these cellular processes. To determine the downstream pathways modulated by Nm23-h1, we expressed Nm23-h1 in a Burkitt lymphoma derived B-cell line BJaB and performed pathway speci c microarray analysis. The genes with signi cant changes in expression patterns were clustered in groups which are responsible for regulating cell cycle, p53 activities and apoptosis. We found a general reduction of cell cycle regulatory proteins including cyclins and cyclin dependent kinase inhibitors (anti proliferation), and upregulation of apoptotic genes which included caspase 3, 9 and Bcl-x. Nm23-h1 was also found to upregulate p53 and downregulate p21 expression. a number of these genes were validated by real time pCR and results from promoter assays indicated that Nm23-h1 expression downregulated cyclin D1 in a dose responsive manner. Further, we show that Nm23-h1 forms a complex with the cellular transcription factor ap1 to modulate cyclin D1 expression levels. BJaB cells expressing Nm23-h1 showed reduced proliferation rate and were susceptible to increased apoptosis which may in part be due to a direct interaction between Nm23-h1 and p53. These results suggest that Nm23-h1 may have a role in the regulation of cell cycle and apoptosis in human B-cells.