The Role of CDCA7 in Akt-mediated Myc-Dependent Apoptosis and Proliferation
Gabor, Tim Vincent
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CDCA7, or cell division cycle associated protein A7, was described in 2001 by Prescott and colleagues as a target of Myc-dependent transcriptional regulation (Prescott et al., 2001). We have identified CDCA7 as associating with the transcription factor Myc and is the target of phosphorylation by the prosurvival serine/threonine kinase Akt. Phosphorylation by Akt at threonine 163 disrupts CDCA7 association with Myc, promotes binding to 14-3-3 and sequestration in the cytoplasm. Coexpression of CDCA7 and Myc in fibroblasts potentiates Myc-dependent apoptosis upon serum withdrawal. In contrast, knockdown of CDCA7 by shRNA abrogated Myc-dependent apoptosis. Myc induced transformation of fibroblasts was reduced in the presence of CDCA7 and significantly inhibited by the expression of the non-Myc binding mutant (156-187) CDCA7. We have shown that CDCA7 enhances the activation of an E-box in a Myc-binding dependent manner. CDCA7 increases Myc occupancy of the proapoptotic BAX promoter, elevates BAX and Cyclin B1 mRNA levels while reducing p15INK4B mRNA levels. This data points to a novel mechanism which implicates Akt phosphorylation of CDCA7 as participating in the dual signal model of Myc of function and thus affecting Myc-dependent growth and transformation. In this study, we have also shown that expression of CDCA7 reduces proliferation rates and shifts cell cycle distribution towards G2/M phase and that phosphorylation of CDCA7 at T163 occurs strictly in G2/M. CDCA7 phosphorylated at threonine 163 colocalizes with the centrosomal protein marker -Tubulin and activated Akt (phospho-serine 473) in mitotic cells. Finally, we have shown that CDCA7 co-associates with monomers of itself which is dependent on amino acids 187-234, adding to the possible mechanisms by which CDCA7 function may be regulated.