Hypoxia often occurs under various physiological and pathophysiological conditions, including solid tumors; it is linked to malignant transformation, metastatic progression, and treatment failure or resistance. Tip110 protein plays important roles in several known physiological and pathophysiological processes, including cancers. Thus, in the present study we investigated the regulation of Tip110 expression under hypoxia. Hypoxia led to Tip110 protein degradation through the ubiquitin-proteasome system. Under hypoxia, Tip110 stabilized p53, which in return destabilized Tip110. In addition, Tip110 regulated hypoxia-inducible factor 1α (HIF-1α), likely through enhancement of its protein stability. Furthermore, Tip110 upregulated p300, a known coactivator for both p53 and HIF-1α. Expression of a p53(22/23) mutant deficient in p300 binding accelerated Tip110 degradation under hypoxia. Tip110 knockdown resulted in the inhibition of cell proliferation and cell death in the presence of p53. Finally, significantly less Tip110, p53, and HIF-1α was detected in the hypoxic region of bone metastasis tumors in a mouse model of human melanoma cells. Taken together, these results suggest Tip110 is an important mediator in the cross talk between p53 and HIF-1α in response to hypoxic stress.