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Cell Division  2009 

Regulation of the retinoblastoma proteins by the human herpesviruses

DOI: 10.1186/1747-1028-4-1

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The members of the retinoblastoma family of tumor suppressors, Rb, p107 and p130, are transcriptional co-repressors that regulate both differentiation and cell cycle progression. Detailed reviews on genetic and molecular analysis of the Rb pathway in normal and cancerous cells are numerous [1-6] so here we will only briefly introduce this pathway prior to describing how it is manipulated by the human herpesviruses.In the G0 and G1 phases of the cell cycle the active, hypophosphorylated form of Rb binds to transcription factors of the E2F family [7-9]. Through heterodimerization with the DP proteins, E2Fs bind to promoters and control the transcription of genes that are involved in many important cellular functions including cell cycle progression [2,10], DNA replication [11,12], the DNA damage response [13], apoptosis [14-18], differentiation and development [19-21], senescence [22], and angiogenesis [23]. Rb, which itself is an E2F-responsive gene [24], binds to E2Fs at these promoters to actively repress transcription by blocking the E2F activation domain, and by recruiting histone-modifying enzymes such as histone deacetylases (HDACs) [25-28] and chromatin remodeling proteins such as the members of the hSWI/SNF complex [29-31]. There are multiple E2F proteins, some considered mainly as transcriptional repressors, and others with more prominent roles as transcriptional activators.Many cellular and viral proteins interact with the pocket domain of Rb [32] that consists of A and B subdomains and affords a large surface area to support strong and specific interactions. One common amino acid sequence found in proteins that interact with the Rb pocket is the LxCxE motif [25,26,33-35]. More than twenty cellular proteins such as HDACs, and a number of viral proteins interact with Rb in an LxCxE-dependent manner [35-37]. The Rb-binding LxCxE motif interacts with a site within the Rb pocket termed the cleft region. The E2F proteins do not contain LxCxE motifs and bind to a


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