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Aurora-A hinders tumor-suppressor to allow chemotherapy resistance
Date:2/27/2012

HOUSTON - A protein abundantly found in treatment-resistant cancers holds an important tumor-suppressor out of the cell nucleus, where it would normally detect DNA damage and force defective cells to kill themselves, a team of scientists reports in the current Cancer Cell.

"Overexpression of Aurora Kinase-A in tumors has been correlated with resistance to DNA-damaging chemotherapy, but we haven't known how this occurs," said senior author Subrata Sen, Ph.D., professor in The University of Texas MD Anderson Cancer Center Department of Molecular Pathology.

"Our discovery that Aurora A blocks the proper functioning of the tumor-suppressor p73 is a step toward understanding and addressing chemotherapy resistance with more effective treatment combinations," Sen said. Drugs that inhibit Aurora kinases are under development and some have advanced to cancer clinical trials.

Like p53, its better-known cousin, the tumor-suppressor p73 monitors DNA damage during cell division and orders apoptosis - programmed cell death - when it detects damage that can't be repaired. It's an ally of DNA-damaging chemotherapy such as cisplatin, which is designed to trigger apoptosis.

"The role of p73 in the maintenance of genomic stability has been better recognized in recent years and this tumor suppressor is believed to be functionally more important in cells that lack p53," Sen said. Inactivation of p53 is common in many types of solid tumors.

Sticking a phosphate group on p73 keeps it out of the nucleus

Having detected DNA damage, p73 works in the cell nucleus to activate genes that cause cell death.

Aurora-A is a kinase, a protein that regulates other proteins by attaching phosphate groups, consisting of one phosphorus atom connected to four oxygen atoms, at specific binding sites.

Sen and colleagues found that Aurora-A phosphorylates p73 at a specific site and when that happens:

  • p73 l
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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

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