Model System Allows Study of Cell Cycle Checkpoint Proteins

Cancer researchers have created a mouse model system that allows them to study cell cycle checkpoint proteins in healthy and cancerous mammary gland tissues.

Checkpoint proteins monitor the status of the cell genome and, in response to DNA damage, halt cell cycle progression and promote repair or apoptosis, thereby preventing mutation accumulation and suppressing tumor development. The checkpoint protein Hus1 associates with the proteins Rad9 and Rad1 to form the 9-1-1 complex, which localizes to DNA lesions and promotes DNA damage signaling and repair.

Attempts to genetically engineer mice to lack Hus1 failed, as complete inactivation of Hus1 resulted in embryonic lethality. Therefore, investigators at the Cornell University College of Veterinary Medicine (Ithaca, NY, USA) developed a system for regulated Hus1 inactivation in the mouse mammary gland to examine roles for Hus1 in tissue homeostasis and tumor suppression.

They reported in the Nov. 16, 2009, online edition of the journal Proceedings of the [U.S.] National Academy of Sciences (PNAS) that Hus1 inactivation in the mammary epithelium resulted in genome damage that induced apoptosis and led to depletion of cells lacking Hus1 from the mammary gland. In cancerous tissue with an inactive form of the tumor-suppressor protein p53, there was a delay in the clearance of cells lacking Hus1 that caused the accumulation of damaged, dying cells in the mammary gland.

"Our work contributes to an important new understanding of cancer cells and their weaknesses," said senior author Dr. Robert Weiss, professor of molecular genetics at the Cornell University College of Veterinary Medicine. "The mutations that allow cancer cells to divide uncontrollably also make the cancer cells more dependent on certain cellular processes. We were able to exploit one such dependency of p53-deficient cells and could efficiently kill these cells by inhibiting Hus1. We have proven the power of inhibiting both pathways in normal tissue. Now we want to extend our knowledge to cancerous tissue and determine if the loss of Hus1 will impact the ability of cancers with p53 mutations to take hold and grow."

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Cornell University College of Veterinary Medicine