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The Tumor Suppressor Killin
Dr. Liang has identified a new protein (termed "Killin") that represents a novel protein for cancer diagnosis, treatment and drug screening. Killinis a small (178 amino acids) nuclear DNA binding protein shown to play a role in cell cycle control.
Over half a million deaths per year in the U.S. are attributable to the progression of cancer. Therapies such as chemotherapy, radiation therapy or tumor excision are only able to treat a small proportion ofcancers, and these techniques use relatively blunt tools and have associated side effects. The shift in ideology from "curing cancer" to "managing cancer" has arisen due to the increasing understanding of the molecular basis of the control of the cell cycle.
There are a number of cell cycle checkpoints used to determine if a cell's internal machinery is in sufficient order to proceed with division. For example, the checkpoint at the G1/S phase transition determines whether the cell should divide, delay division or enter a resting period. One factor controlling these decisions is the accumulation of damage to the nuclear DNA.The hallmark of cancer is uncontrolled cellular division. Tumor development occurs because of the disruption of the regulatory checkpoints that normally maintain the balance of cell division and proliferation. The molecular species that contribute to these checkpoints therefore represent excellent targets for the treat- ment of cancer.
The tumor suppressor gene p53 has been demonstrated to be the most frequently affected molecular species in human cancer, and as such, is amajor focus of oncology research. The p53 gene provides a mechanism for the cell to assess DNA damage, although it does not detect DNA damage directly. Instead, phosphorylation via signaling molecules leads to its activation and the subsequent upregulation of genes involved in cell cycle arrest and apoptosis.
The technology described here is a novel p53 target gene, Killin, which encodes a small nuclear DNA binding protein, 178 amino acids in length.
Current Stage ofDevelopment
This protein has high affinity for both double and single-stranded DNA and experimentally is capable of inhibiting DNA synthesis in vitro and S-phase arrest coupled to apoptosis in vivo.
Killin therefore represents the first p53 target gene that is directly involved inS-phase checkpoint control-coupled apoptosis. Upon induction by p53, Killin inhibits DNA synthesis at the replication forks, causing S-phase arrest and subsequent apoptosis.
A provisional patent application has been filed with a priority date of September 13, 2005. This patent application describes the first p53 target gene that is involved in theS-phase checkpoint; as such, it completes the understanding of the role of p53 as a critical molecule in the control of the cell cycle. Within this application are methods and compositions relating to the subsequent use of Killin and its protein product in diagnosis, screening and treatment of cancer.
Inventors:Peng LiangYong-jig Cho