The researchers found lung cancer cells overexpressing Aurora-A have p73 evenly distributed in the nucleus and cytoplasm, but when treated with an Aurora-A inhibitor, p73 is found mainly in the nucleus. They repeated this experiment with similar results in breast and pancreatic cancer cell lines in which Aurora-A is overexpressed.
Mortalin ties phosphorylated p73 in cytoplasm
Sen and colleagues found that the protein mortalin binds to p73 that's been phosphorylated by Aurora-A, and plays a role moving p73 out to the cytoplasm and keeping it there. Mortalin has been implicated in tumor formation and immortalization.
In addition to DNA damage, p73 also regulates the mitotic spindle assembly checkpoint, which regulates a specific mechanism involved in the normal separation of chromosomes during cell division. The team found that Aurora-A phosphorylation of p73 also inactivates this checkpoint function.
They also found Aurora-A expressed at normal levels has a regular role to play in phosphorylating p73 in normal spindle assembly checkpoint function during cell division.
Aurora-A effect on p73 found in human pancreatic cancer
When they treated lung cancer cells with cisplatin, cells with phosphorylated p73 were least sensitive to cell death caused by the chemotherapy. In the absence of Aurora-A overexpression, cells were more sensitive to cisplatin treatment.
The team analyzed p73 and Aurora-A in 114 samples of human pancreatic ductal adenocarcinoma at MD Anderson and found 51 (44.7 percent) had high Aurora-A expression and 37 of those had high levels of p73 in the cytoplasm. Of the 63 low-Aurora-A tumors, only 18 (28.6 percent) had high levels of p73 in the cytoplasm.
Inactivation of the DNA and spindle damage-induced cell death pathways ma
|Contact: Scott Merville|
University of Texas M. D. Anderson Cancer Center