The role of translationally controlled tumor protein in proliferation of Drosophila intestinal stem cells

Abstract

Translationally controlled tumor protein (TCTP) is a highly conserved protein functioning in multiple cellular processes, ranging from growth to immune responses. To explore the role of TCTP in tissue maintenance and regeneration, we employed the adultDrosophilamidgut, where multiple signaling pathways interact to precisely regulate stem cell division for tissue homeostasis. Tctp levels were significantly increased in stem cells and enteroblasts upon tissue damage or activation of the Hippo pathway that promotes regeneration of intestinal epithelium. Stem cells with reduced Tctp levels failed to proliferate during normal tissue homeostasis and regeneration. Mechanistically, Tctp forms a complex with multiple proteins involved in translation and genetically interacts with ribosomal subunits. In addition, Tctp increases both Akt1 protein abundance and phosphorylation in vivo. Altogether, Tctp regulates stem cell proliferation by interacting with key growth regulatory signaling pathways and the translation process in vivo.

Dysregulation of TCTP in Biological Processes and Diseases

“…A more specific study demonstrated the interaction of TCTP with translation elongation factor eEF1A and its guanine nucleotide exchange factor (GEF), eEF1B [24]. Subsequently, the interaction of TCTP with elongation factors of the EF1 family and with other components of the translational apparatus was confirmed both in human cells [7,25] and in Drosophila [15]. Consistent with this is the observation that the genes of ribosomal proteins, elongation factors, and of TCTP all belong to the class of 'TOP genes', whose mRNAs have a common signature, the 5 -terminal oligo-pyrimidine tract (5 -TOP) [26], and are therefore translationally regulated [27].…”

“…They demonstrated that in axons of retinal ganglion cells, local TCTP synthesis is regulated by two axon guidance cues in an mTORC1-dependent fashion. In a completely different biological system, the intestinal stem cells in the midgut of Drosophila, yet another example of posttranscriptional regulation of TCTP synthesis was observed [15]. In this case, the Hippo signalling pathway has been implicated.…”

“…The capacity of TCTP to regulate diverse pathways, from mTOR and genome integrity to cell migration, has one common feature: cell survival. This is probably best reflected in tumor biology by reshaping tumor organisation and stemness [78], the latter being a conserved TCTP function from developmental biology [92] and tissue maintenance [15] to cancer stem cells [40]. A key aspect of TCTP function as a survival factor is its interaction with both, the anti-apoptotic and pro-apoptotic machinery.…”

“…The latter observation is consistent with another report showing that disruption of TCTP using CRISPR/Cas9 in the silkworm Bombyx mori resulted in developmental arrest and in subsequent lethality in the third instar larvae, caused by defects in proliferation of intestinal epithelial cells [ 14 ]. Similarly, a recent report demonstrated the importance of TCTP in stem cells of the midgut in Drosophila for tissue homeostasis and regeneration [ 15 ]. As potential mechanisms, the authors suggest the regulation of protein synthesis by TCTP ( Section 2.2 .…”

Wear and Tear of the Intestinal Visceral Musculature by Intrinsic and Extrinsic Factors

“…Hippo signaling keeps ISCs in check during normal homeostasis (Karpowicz et al, 2010; Ren et al, 2010; Shaw et al, 2010). Thus, inhibition of Hippo signaling or activation of the downstream transcription factor Yorkie leads to proliferation of ISCs, resulting in formation of Drosophila midgut epithelial hyperplasia (Kwon et al, 2015; Kwon et al, 2013; Kwon et al, 2019). To address how midgut expansion due to hyperplasia affects the visceral musculature, we expressed an active form of yorkie ( yki 3S/A ) with esg ts , which induced progressive midgut epithelial hyperplasia (Figure 2A, 2B, and S2).…”