PDF of Entire Gipson Thesis

ABSTRACT

p53 is a transcription factor associated with over 50% of human cancers. Under stress conditions, such as DNA damage, ultraviolet light, and aberrant oncogene signaling, normal p53 is responsible for inducing programmed cell death (apoptosis). Cancer results when p53 is unable to stop cells from proliferating when they become damaged. Accordingly, the use of p53 as a targeted approach towards cancer therapy is attractive. This strategy is based on manipulating mutant p53 to restore function, which would allow p53 to induce apoptosis in cancer cells. Here, I look at the mechanisms of certain p53 stabilizing compounds and potential ways in which these compounds interact with p53. Through NMR, in vivo studies, and molecular modeling I have been able to elucidate the possible stabilization mechanisms.

The holy grail of cancer research is to kill target cells that exhibit abnormal and uncontrolled cell growth. The number of cellular targets in these cells is enormous and successfully targeting and manipulating one of these is analogous to trying to cut off one node on the Internet to disrupt the entire network. If this approach is to be met with any degree of success, such a node must be highly connected with other nodes or pathways. This manipulation will thus result in much greater impact that could lead to an eventual treatment of the disease.

p53 is a tumor suppressor protein associated with over 50% of human cancers. 1 In short, p53 helps regulate the cell cycle and insure that cells transition through the cell cycle in a proper manner when damaged. Its association with a wealth of other cellular proteins involved in cell growth regulation makes it a prime candidate for cancer therapy. It is one of the most connected nodes in the cellular network.

The approach taken in this study is to find small chemicals that will bind to mutant p53. Binding of such chemicals will then induce stabilization that will then reinstate proper function to the protein. Since mutant p53 is present in numerous types of cancers, this new approach may have broad applicability.

OVERVIEW

Cancer is a series of diseases marked by uncontrolled proliferation of abnormal cells. The United States in 2003 is estimated to have some 1,334,100 new cancer cases. Factors that cause cancer are both external and internal. External factors may include tobacco, radiation exposure, and invasion by infection organisms. Internal factors may be the result of hormones, immune system, and genetic mutations. 2

In February of 2001, the first draft of the Human Genome was published as a collaborative effort of academic and private enterprises. This 2.91 billion base pair (bp) sequence has provided an abundance of genetic information that has been used to help elucidate mechanisms of evolution and disease. Combined with past studies, this has allowed for the identification of novel genes and targets associated with cancer and other diseases. 3

In breast cancer, for instance, inactivation or mutations in the Brca1, Brca2 and ATM genes predispose people to breast cancer. All three of these genes are classified as tumor suppressor genes. 4

The role of tumor suppressor genes is to help prevent and remedy genetic damage. When the cell incurs DNA damage, theses genes stop that damage from proliferating through cascading pathways leading to cell cycle arrest and apoptosis. Consequently, tumor suppressor genes have been of great interest both for their potential role in diagnosis and treatment via manipulation of inactive or mutated genes.

Current cancer treatments primarily include chemotherapy and radiation therapy. Both of these treatments can lead to uncomfortable side effects such as hair loss and nausea. With radiation therapy in particular, the approach is very nonspecific. Radiation is targeted to a cancerous region in the body and kills both cancer and healthy cells. Since cancer cells grow and divide more rapidly, they are more susceptible to DNA damage induced by the radiation and thus die more quickly. 5

These methods, although improved from their initial inception, are not sophisticated in their mechanism of action. Accordingly, the goal is to try to elucidate new approaches to combat cancer in a more specific way.

The link to manipulation of tumor suppressors as a means to achieve this goal is an instinctive one. As with Brca1, Brca2, and ATM, there are many tumor suppressors. With numerous tumor suppressors involved in a wide range of cancers, a broader based approach towards cancer therapy becomes difficult. However, one tumor suppressor has been identified to be associated with over 50% of human cancers. 1 This tumor suppressor is called p53.

<<BACK (Gipson Intro) NEXT (The Discovery of p53)>>

1 Hollstein, M. et al. p53 Mutations in Human Cancers. Science 254 49-53 (1991).

2 Cancer Facts & Figures 2003, American Cancer Society, Inc. 2003

3 Venter, J. Craig, Adams, Mark D., Myers, Eugene W. et al., The Sequence of the Human Genome. Science 291 1304-1351 (2001).

4 Cortez, David et al. Requirement of ATM-Dependent Phosphorylation of Brca1 in the DNA Damage Response to Double-Strand Breaks. Science 286 1162-1166 (1999).

5 http://www.breastcancer.org/tre_rad_howWrk.html

Sign Guest Book
View Guest Book