THE MECHANISM OF RB-MEDIATED CELL CYCLE INHIBITION

 
 
 
 

THE MECHANISM OF RB-MEDIATED CELL CYCLE INHIBITION

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Title: THE MECHANISM OF RB-MEDIATED CELL CYCLE INHIBITION
Author: ANGUS, STEVEN PATRICK
Description: The retinoblastoma tumor suppressor (RB) is a critical negative regulator of cellular proliferation. The importance of RB in controlling cell growth and division is underscored by the observation that greater than 60% of human tumors exhibit functional inactivation of the RB pathway. RB functions as a transcriptional repressor, able to bind to the E2F family of transcription factors and regulate the expression of genes required for S-phase entry and progression. In response to anti-mitogenic stress signals (e.g. DNA damage), RB becomes hypophosphorylated/activated, able to down-regulate these genes, and elicit cell cycle arrest. RB/E2F-regulated genes include cyclin-dependent kinase (CDK) and cyclins, components of the DNA replication machinery, and metabolic enzymes required for the production of deoxyribonucleotides (dNTPs). Here, we investigated the relevant targets of RB-mediated repression that contribute to the arrested phenotype. We describe functional signaling pathways of active RB that target the activity of CDK2/cyclin A to disrupt the function of PCNA, a late step in the DNA synthetic process. In a parallel pathway, RB represses the expression of dNTP synthetic enzymes to limit available DNA precursor molecules during cell cycle arrest. Under conditions of chronic RB activation, the expression of multiple DNA replication components is attenuated, leading to a replicative exit state. Loss of RB signaling permits cells to escape this long-term arrest state, demonstrating the requirement of RB in the maintenance of two, kinetically distinct checkpoints. RB has been shown to bind to over 100 cellular proteins. Using innovative imaging techniques, we demonstrate that E2F sites on chromatin are the principal targets of active RB during cell cycle arrest. These studies elucidate the critical targets and resultant phenotypes mediated by the retinoblastoma tumor suppressor protein to inhibit cellular proliferation.
Permanent Link: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1061224578
http://hdl.handle.net/2374.OX/13103
Date: 2003

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