Regulation of AneuploidyPublic
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The retinoblastoma (RB) protein is a well characterized tumor suppressor, which is found to be mutated in various types of cancer. The best characterized role of pRB relates to its role as a key regulator of the G1 checkpoint. However, recent studies have implicated pRB activity during later phases of the cell cycle, when pRB is present in a hyperphosphorylated state. Recent work has experimentally identified proteins that specifically interact with either hypophosphorylated pRB, as would be found during G1, or hyperphosphorylated pRB, as would be found in G1, S, or G2 stages of the cell cycle. To better understand the functional subcomplexes they may form, I used the web-based Search Tool for the Retrieval of Interacting Genes (STRING) software to map and identify distinct protein subcomplexes within the hypo- and hyperphosphorylated pRB interactomes. Next, to define the nature of the interactions with pRB, I evaluated each protein within these two interactomes for the presence of an LxCxE sequence motif, which has been demonstrated to moderate protein interactions with pRB. Many of the best characterized pRB-associated proteins that cooperate with pRB in cell cycle control contain an LxCxE motif. Consistent with this, my analysis identified LxCxE binding motifs in 20% of proteins within the hypophosphorylated pRB interactome, with at least one LxCxE domain-containing protein in each identified interacting cluster, suggesting interactions of the remaining 80% of proteins with pRB may be moderated through an LxCxE-containing protein. In contrast, less than 1% of proteins and only a quarter of defined protein clusters within the hyperphosphorylated pRB interactome contained LxCxE motifs. These analyses propose that the majority of proteins that interact with pRB at later stages of the cell cycle, when pRB is hyperphosphorylated, do so in a manner that is independent of pRB’s LxCxE binding domain.
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