TAF7: A Check-point Regulator in Transcription Initiation and Translation

Division Of Clinical Sciences - Nci

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Abstract

Maintaining homeostasis in cells requires the integration of multiple cellular processes including transcription, RNA export to polysomes, proper folding of nascent proteins and proper sorting of proteins to endosomes and other cellular compartments. TAF7 plays a critical role in coordinating transcription, regulating initiation, pause release, early elongation and productive elongation through its interactions with, and inhibition of, the enzymatic activities necessary for each step. During productive elongation, TAF7 travels with the elongation complex, where it binds to a large spectrum of nascent RNA species at consensus CUG motifs in the 3' region of its target transcripts. Remarkably, TAF7 transports bound RNA from the nucleus to the cytoplasm in an exportin-dependent process and delivers the RNA to cytoplasmic polysomes. Disruption of TAF7 binding to its target RNAs or depletion of cytoplasmic TAF7 reduces the levels of its protein products and reduces protein synthesis globally. In this way, TAF7 coordinates transcription in the nucleus with translation in the cytoplasm. Beyond coordination of transcription and translation, cellular homeostasis requires proper protein folding, protein segregation within cellular compartments and transcriptional activation in response to extracellular signaling. Mediators of each of these activities have been identified. Thus, a variety of chaperones are known to ensure co-translational folding of nascent proteins. Among these is the CCT (also known as TriC) complex, consisting of two rings of eight subunits each. CCT folds actin and tubulin co-translationally but also interacts with other mature proteins post-translationally. The WASH complex is one of a number of different Wiskott-Aldrich syndrome proteins (WASP) family members that are responsible for actin remodeling. The WASH complex activates actin filament assembly and regulates endosomal sorting. Extracellular signaling by cytokines and growth factors activates the Src pathway, resulting in the phosphorylation of transcription factor, STAT3, and its translocation into the nucleus, where it activates target gene expression. While all three of these factors - CCT, WASH and STAT3 - play an important role in the maintenance of cellular homeostasis, they also have been shown to play a role in cancer. During cellular transformation, normal homeostasis is perturbed to respond to the requirements of the cancer cell. Many transcriptional, translational, metabolic and signaling pathways are constitutively upregulated. Our finding that TAF7 normally functions to transport RNA to the cytoplasm and regulate translation led us to ask whether the levels of TAF7 in the cytoplasm correlate with the disruptions in cellular homeostasis associated with transformed cancer cells . Analysis of cellular transformation in three distinct models - breast cancer cell lines, induced T-ALL transformation and Src-induced transformation of a normal breast cell line - provided evidence that cytoplasmic TAF7 levels increase during transformation. Thus, there is a direct correlation between pathogenicity and cytoplasmic TAF7. Consistent with our findings, analysis of patient data have reported that TAF7 is part of a risk signature in HNSCC and its high expression negatively correlated with survival in TNBC. However, neither of those analyses examined the cellular localization of TAF7 in the cancer cells. We have found that the relative levels of cytoplasmic TAF7 increase with cellular transformation and pathogenicity, leading to increased interactions with a variety of cytoplasmic proteins. Among the major cytoplasmic interacters we identified are the WASH complex, the CCT complex and STAT3, all of which are involved in cancer. Together, these findings indicate a potential role for TAF7 in cancer.