TY - JOUR
T1 - Tip110 regulates the cross talk between p53 and hypoxia-inducible factor 1α under hypoxia and promotes survival of cancer cells
AU - Timani, Khalid Amine
AU - Liu, Ying
AU - Fan, Yan
AU - Mohammad, Khalid S.
AU - He, Johnny J.
N1 - Publisher Copyright:
© 2015, American Society for Microbiology.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84930863472&partnerID=8YFLogxK
U2 - 10.1128/MCB.00001-15
DO - 10.1128/MCB.00001-15
M3 - Article
C2 - 25939381
AN - SCOPUS:84930863472
SN - 0270-7306
VL - 35
SP - 2254
EP - 2264
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 13
ER -