Abstract
LIN-35 is the sole C. elegans representative of the pocket protein family, which includes the mammalian Retinoblastoma protein pRb and its paralogs p107 and p130. In addition to having a well-established and central role in cell cycle regulation, pocket proteins have been increasingly implicated in the control of critical and diverse developmental and cellular processes. To gain a greater understanding of the roles of pocket proteins during development, we have characterized a synthetic genetic interaction between lin-35 and slr-2, which we show encodes a C2H2-type Zn-finger protein. Whereas animals harboring single mutations in lin-35 or slr-2 are viable and fertile, lin-35; slr-2 double mutants arrest uniformly in early larval development without obvious morphological defects. Using a combination of approaches including transcriptome profiling, mosaic analysis, starvation assays, and expression analysis, we demonstrate that both LIN-35 and SLR-2 act in the intestine to regulate the expression of many genes required for normal nutrient utilization. These findings represent a novel role for pRb family members in the maintenance of organ function. Our studies also shed light on the mechanistic basis of genetic redundancy among transcriptional regulators and suggest that synthetic interactions may result from the synergistic misregulation of one or more common targets.
Highlights
The Retinoblastoma protein, pRb, was among the first recognized tumor suppressor proteins [1,2,3], and loss or repression of pRb function is thought to play a causative role in most human cancers [4,5,6,7,8]
To gain a deeper understanding of this phenomenon, we have focused on a synthetic genetic interaction between lin35, a C. elegans member of the pRb/pocket-protein tumor suppressor family and slr-2, a Zn-finger protein
Using a wide range of approaches including transcriptome profiling, mosaic analysis, and expression analysis, we demonstrate that both LIN-35 and SLR-2 act within the intestine to regulate the expression of many genes that function in nutrient utilization
Summary
The Retinoblastoma protein, pRb, was among the first recognized tumor suppressor proteins [1,2,3], and loss or repression of pRb function is thought to play a causative role in most human cancers [4,5,6,7,8]. The role of pRb as a tumor suppressor has been largely attributed to its functions in cell cycle regulation, which it carries out in conjunction with its two family members, p107 and p130, collectively known as the pocket proteins [9,10,11]. A growing number of studies have demonstrated non2cell cycle roles for pRb family members, which in some cases may prove relevant to the tumor-suppressing activity of pocket proteins [12,19,22,23]. In the case of LIN-35, the majority of these functions are revealed only when LIN-35 activity is compromised in specific mutant backgrounds This phenomenon can be explained on the basis of genetic or functional redundancy, a widespread feature of eukaryotic genomes, which is attributable to the complex and overlapping nature of many regulatory networks. Single mutants in most SynMuv genes, including lin-35, do not display observable defects in vulval development
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