Many genetic alterations at the CDKN2A locus on human chromosome 9 have been shown to be at least partially responsible for transformation of cells to a cancerous phenotype. This locus encodes two proteins, p16 and p14, that play a pivotal role in tumor surveillance.
Breakdowns in the p14 pathway have been estimated to be present in approximately 40% of human cancers and only recently have its binding partners and effects begun to be defined. Its interaction with the p53 pathway, which is estimated to be inactivated or mutated in 50% of all cancers, makes it difficult to determine its own independent effects, but also makes it a prime target for cancer intervention. Taken together, one or both of these pathways have been estimated to be aberrant in virtually all human cancers, therefore, understanding their individual and cooperative effects may prove to be of paramount importance.
In the present study we evaluated the overexpression of the p14ARF tumor suppressor in the cancerous HCT116 parent cell line along with its p53 knockout derivative. Our results indicate that p14 indeed has a very potent effect in the presence of p53, and a substantial effect in its absence.
In the clonogenicity experiments p14 had a very powerful affect, both in the presence and absence of p53. In the presence of p53, p14 was able to reduce the number of colonies grown by 98%, and in the absence of p53 it was able to reduce the colony count by 83%. In the cell velocity assays, p14 was able to retard cell growth in high-density populations in the absence of p53. Furthermore, p14 was also able to reduce the size of tumors grown in nude mice by a substantial margin in the absence of p53.
These experiments demonstrate that p14ARF has tumor suppressor activity that is independent of the p53 pathway. ARF expression exhibited a more profound affect on cell viability in the presence of p53, due to both tumor suppressor pathways being active. However, even in the absence of p53, p14 was able to mitigate the growth of cells both in vivo and in vitro.
Ronald L. Carter
Michael B. Lilly
Charles W. Slattery
Doctor of Philosophy (PhD)
Year Degree Awarded
Date (Title Page)
Library of Congress/MESH Subject Headings
Neoplasm -- genetics; Genes, Tumor Suppressor; Neoplasm Proteins.
Loma Linda University Libraries
This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.
Miller, Monte W., "p14ARF : A p53-Independent Tumor Suppressor" (2004). Loma Linda University Electronic Theses, Dissertations & Projects. 706.
Loma Linda University Electronic Theses and Dissertations
Loma Linda University. Del E. Webb Memorial Library. University Archives