p53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells.

摘要: The negative-regulatory feedback loop between p53 and hdm2 forms part of a finely balanced regulatory network proteins that controls cell cycle progression commitment to apoptosis. Expression hdm2, its mouse orthologue mdm2, is known be induced by p53, but recent evidence has demonstrated mdm2 expression can also regulated via p53-independent pathways. However the independent mechanisms control transcription human gene have not been studied. Differential levels mRNA protein reported in several types malignancy, including breast cancers which correlates with positive estrogen receptor alpha (ERalpha) status. Experimental models overexpression promote cancer development. Here, we show elevated level ERalpha(+ve) lines such as MCF-7 T47D because from p53-inducible P2 promoter hdm2. inactive ERalpha(-ve) SKBr3. Hdm2-P2 activity cells well regulators mdm2-P2 promoter, ERalpha ras-raf-mitogen-activated protein/extracellular signal-regulated kinase (MEK) mitogen-activated (MAPK) signaling. We hdm2-P2 dependent on integrity both an evolutionarily conserved composite binding site for AP1 ETS family factors (AP1-ETS) nonconserved upstream (nnGGGGC)(5) repeat sequence. Lack shown consequence reduced transcriptional activation through AP1-ETS element. Overexpression ETS2 SKBr3 reconstitutes element-dependent activity, resulting increased cells. Our findings support hypothesis tumors play important role development these tumors.