Mechanistic study of inhibitory phosphorylation of c-jun in breast cancer

• Main Authors: Li-Wei Wu, 吳莉葳
• Other Authors: Ming-Feng Hou
• Format: Others
• Language: zh-TW
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/50853123997057878486

碩士 === 高雄醫學大學 === 醫學研究所 === 101 === Serine/threonine mitogen-activated protein kinases (MAPKs) have been closely associated with cancer. Inflammatory cytokines, trophic factor deprivation and a number of cell stresses lead preferentially to activation of c-jun NH2-terminal kinase (JNK) and p38 MAP kinases. JNK activates c-jun through the phosphorylation of the N-terminal transactivation domain of c-jun upon UV irradiation and oncoprotein expression. The c-jun proto-oncogene has pleiotropic effects on tumor development and is one of the AP-1 family members, which has been demonstrated in the regulation of apoptosis, angiogenesis, invasion and metastasis. In general, N-terminal phosphorylation of c-jun is necessary for its transcriptional activity, whereas the JNK signaling phosphorylates the Ser-63 and Ser-73 residues of the c-jun. Other MAPKs target these sites; the Ser-63 and/or Ser-73 residues are phosphorylated by the ERK1/2. Intriguingly, ERK1/2 is able to phosphorylate the C-terminal inhibitory site Ser-243 of the c-jun, and results in decreasing the stability and DNA-binding activity of c-jun. Unlike N-terminal phosphorylation, phosphorylation of the C-terminal sites inhibits the DNA-binding activity of c-jun/AP-1 family. Our results showed that cytoplasmic intensity of p-ser-243-c-jun was inversely correlated with lymph node metastasis, recurrence (p<0.001, p=0.044) and the nuclear p-ser-243-c-jun was inversely correlated with Her2/neu status (p=0.047). Increased cytoplasmic intensity of p-ser-243-c-jun was positively correlated with those of p-ERK1/2 (p=0.047). In addition, the nuclear frequency of p-ser-243-c-jun and COX-2 were positively correlated (p=0.008). We further found that the phosphorylation of c-jun at the Ser-243 residue did not affect cell growth. Nevertheless, S243A-c-jun mutant dramatically increased the invasion and migration of the MCF-7 and Her2 stable overexpressing MCF-7 clone cells as compared to the control and wild-type c-jun. In addition, ectopic overexpression of S243A-c-jun induced both protein and mRNA levels of MMP9. Taken together, our results suggested that p-ser243-c-jun might play a tumor suppressive role and serve as a prognosis biomarker in breast cancer.