Hypoxia stimulates several pathways that are critical to cancer cell growth and survival, including activation of vascular endothelial growth factor (VEGF) transcription. Overexpression of VEGF and the extent of neoangiogenesis are closely correlated with tumor development and cancer metastases. Recent studies suggest MDM2 as one of the major regulators of pro-angiogenic mechanisms. To assess the direct correlation of HIF-1α and NF-κB, and the actual mechanism of MDM2 involved in the control over VEGF transcription, we exposed the LNCaP and LNCaP-MST cells (MDM2 transfected) to hypoxia. Our experiments confirm that MDM2 activation can lead to significant decrease in the levels of p53 in MDM2 transfected LNCaP-MST cells than the wild-type LNCaP cells. The results further suggest that MDM2 can be a strong regulator of both p53 dependent and independent transcriptional activity. Similarly, an increased level of other transcription factors such as HIF-1α, P300, STAT3, pAKT and NF-κB was observed. As a point of convergence for many oncogenic signaling pathways, STAT3 is constitutively activated at high frequency in a wide diversity of cancers. Our results indicate that STAT3 can directly regulate VEGF expression that is controlled by MDM2. Furthermore, it is evident from our results that NF-κB may interfere with the transcriptional activity of p53, by downregulating its levels. On the other hand, several pro-angiogenic mechanisms, including VEGF transcription which is controlled by MDM2, seem to be mediated by NF-κB.