Roles of pRB in the Regulation of Nucleosome and Chromatin Structures.

Chiharu Uchida

doi:10.1155/2016/5959721

Abstract

Retinoblastoma protein (pRB) interacts with E2F and other protein factors to play a pivotal role in regulating the expression of target genes that induce cell cycle arrest, apoptosis, and differentiation. pRB controls the local promoter activity and has the ability to change the structure of nucleosomes and/or chromosomes via histone modification, epigenetic changes, chromatin remodeling, and chromosome organization. Functional inactivation of pRB perturbs these cellular events and causes dysregulated cell growth and chromosome instability, which are hallmarks of cancer cells. The role of pRB in regulation of nucleosome/chromatin structures has been shown to link to tumor suppression. This review focuses on the ability of pRB to control nucleosome/chromatin structures via physical interactions with histone modifiers and chromatin factors and describes cancer therapies based on targeting these protein factors.

Highlights

Retinoblastoma protein was the first identified tumor suppressor that negatively regulates the G0/G1 to S phase transition of the cell cycle [1,2,3,4]
The most studied mechanism by which pRB negatively regulates the cell cycle progression involves the biding of pRB to E2F transcription factors (E2F1, E2F2, and E2F3a), which inhibits E2F-mediated expression of S phase-promoting genes, such as DNA polymerase, dihydrofolate reductase, and cdc2 [5,6,7,8]. pRB inhibits E2F transcriptional activity via a direct interaction with E2F; pRB blocks cell cycle progression by repressing the target gene transcription through the recruitment of transcriptional corepressors and/or chromatin remodeling protein factors at promoter regions [9] (Figure 1)
The repressors and protein factors that cooperatively participate in the pRB-mediated transient repression and silencing of the target genes include histone deacetylase (HDAC) [10, 11], replication factor C [12], ATPase subunit of the SWI/SNF complexes Brm and BRG1 (Brm-related gene 1) proteins [13, 14], DNA methyltransferase DNA methyl transferase 1 (DNMT1) [11], and heterochromatin protein HP1 [15], which all belong to “LXCXE proteins” that possess the LXCXE-binding motif for pRB [16]

Summary

Introduction

Retinoblastoma protein (pRB) was the first identified tumor suppressor that negatively regulates the G0/G1 to S phase transition of the cell cycle [1,2,3,4]. The most studied mechanism by which pRB negatively regulates the cell cycle progression involves the biding of pRB to E2F transcription factors (E2F1, E2F2, and E2F3a), which inhibits E2F-mediated expression of S phase-promoting genes, such as DNA polymerase, dihydrofolate reductase, and cdc2 [5,6,7,8]. PRB inhibits E2F transcriptional activity via a direct interaction with E2F; pRB blocks cell cycle progression by repressing the target gene transcription through the recruitment of transcriptional corepressors and/or chromatin remodeling protein factors at promoter regions [9] (Figure 1).

Results

Conclusion