Role of the POP1 Gene in Breast Cancer Genomic Stability

Institution: Stanford University
Investigator(s): Peter Jackson, Ph.D. -
Award Cycle: 1999 (Cycle V) Grant #: 5JB-0121 Award: $112,710
Award Type: IDEAS II
Research Priorities
Biology of the Breast Cell>Biology of the Normal Breast: the starting point

Initial Award Abstract (1999)
The majority of human breast cancers have an increased content of abnormal DNA in each tumor cell. This increased DNA content is a strong predictor of the prognosis of many solid tumors. In part, the increased DNA content may be due to specific amplifications of specific genes. Our working hypothesis is that alterations in factors controlling the accuracy of DNA replication are important for the development of human breast cancer. The mechanisms underlying this form of genomic instability are essentially unknown.

We have identified a mechanism in yeast critical for regulating DNA content. The activation of two yeast genes, POP1 and POP 2, directs the destruction of regulatory proteins that are responsible for limiting DNA replication. Mutations in POP 1 or POP2 cause yeast to accumulate these regulatory proteins and to replicate their DNA too many times. We have identified human and mouse genes similar to the yeast POP genes. We have begun to test whether these genes serve a similar role in mammalian cells. Using genetic techniques, we have evidence that the human POP1 may be important for restraining cancer growth, and may play a role in restricting breast cancer growth.

The purpose of this project is to find genetic evidence that the human POP genes are actually altered in breast tumors. We will then develop tools to allow us to rapidly diagnose changes in the POP genes, the proteins they encode, or the effects they have in tumor cells.

We believe that the POP genes may be critical caretakers of the cellular DNA. Accordingly, mutations in cellular caretakers may promote the alteration of other genes that either activate cancer (oncogenes) or limit cancer (tumor suppressor genes). This loss of genetic stability is a feature in the late stages of tumors and may be critical for the aggressiveness of specific tumors, including breast tumors

Final Report (2002)
Our studies on the human Pop1 protein were designed to understand its basic role in cell cycle control. Our initial motivation was based on our original analysis suggesting that human Pop1 might be involved in cancer in the bladder given its chromosomal localization (9p34) to a region thought to be a tumor suppressor in bladder cancer and its overexpression in a small number of bladder cancers. Our studies on human Pop1 suggested that gene itself might be of some interest, but our functional studies in cells failed to identify any clear cellular defects when we overexpressed a wild type or dominant negative version of the protein. A two-hybrid analysis also failed to identify any genes that might suggest a link to a known phenotype or function.

The student pursuing this project, Jerry Y. Hsu, shifted his focus to another F-box protein that we were studying in the laboratory, called Fbx5 or human Emit. This project proved to be very fruitful and has resulted in an important story for how the Fbx5 gene controls the entry into S phase by inducing the stabilization of cell cycle regulators, including cyclin A. We have also found that gene to be overexpressed in 30-40% of tumors of the breast, ovary, uterus, colon, and lung.

E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1).
Periodical:Nature Cell Biology
Index Medicus: Nat Cell Biol
Authors: Hsu JY, Reimann JD, Sorensen CS, Lukas J, Jackson PK.
Yr: 2002 Vol: 4 Nbr: 5 Abs: Pg:358-66

The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases.
Periodical:Trends in Cell Biology
Index Medicus: Trends Cell Biol
Authors: Jackson PK, Eldridge AG, Freed E, Furstenthal L, Hsu JY, Kaiser BK, Reimann JD.
Yr: 2000 Vol: 10 Nbr: 10 Abs: Pg:429-39

Emi1 is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex.
Index Medicus: Cell
Authors: Reimann JD, Freed E, Hsu JY, Kramer ER, Peters JM, Jackson PK.
Yr: 2001 Vol: 105 Nbr: 5 Abs: Pg:645-55