The Mechanism of Retinoblastoma Protein-Mediated Terminal Cell Cycle Arrest
Abstract
Inactivation of retinoblastoma gene (Rb) is observed in several human cancers including those of the breast. A characteristic feature of many human cancers is the inability to maintain a terminal cell cycle arrest, whereas the Rb product (pRb) has been implicated in the maintenance of a terminal cell cycle arrest. However, in contrast to our knowledge of how pRb regulates proliferation in a cycling population, little is known how it maintains a permanent cell cycle arrest. The proposed studies are aimed at elucidating the molecular mechanism by which pRb accomplishes this task and plays the role of tumor suppressor of tumor formation. Our working hypothesis is that pRb, in cooperation with MyoD, participates in the transcriptional repression of one or more immediate early genes required for the induction of cyclin Dl. And this event ultimately prevents the re-entry into the cell cycle, thus maintaining a terminal cell cycle arrest. To test this hypothesis myogenic differentiation has been used as model, because it represents a differentiation system in which pRb has been implicated in a terminal cell cycle arrest both in vitro and in vivo. In the past year I have discovered that: (1) The induction of Fra-1 and not any other immediate early genes is blocked following restimulation of differentiated myoblasts. (2) Ectopic expression of the cell cycle inhibitory protein pl6, which bring about a cell cycle arrest distinct from a terminal cell cycle arrest, has no effect on expressions of both Fra-1 and cyclin Dl. In an effort to further study the regulation of the Fra-1 gene I have created Fra-1 promoter reporter and its deletion mutants. Also constructed a retrovirus vector for ectopic expression of Fra-1 to establish a causal relationship between Fra-1 and cyclin Dl. These results and reagents provide the basis upon which to discover the detailed mechanism by which pRb participates in a terminal cell cycle arrest.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2004
- Accession Number
- ADA430026
Entities
People
- Hasan N. Rajabi
Organizations
- Dana–Farber Cancer Institute