Transcriptional Switches: Chemical Approaches to Gene Regulation

Abstract

Given the role of transcriptional misregulation in the pathogenesis of human disease, there is enormous interest in the development of molecules that exogenously control transcription in a defined manner. The past decade has seen many exciting advancements in the identification of molecules that mimic or inhibit the interactions between natural transcriptional activators and their binding partners. In this minireview, we focus on four activator⅐target protein complexes, highlighting recent advances as well as challenges in the field.Just as specific transcriptional patterns signify the differentiation of stem cells into individual tissues, unique transcriptional signatures are associated with every human disease either as a cause or as an effect. For example, Ͼ50% of human cancers exhibit loss-of-function mutations in the tumor suppressor and transcriptional activator p53 (1, 2). There is thus enormous interest in identifying exogenous agents that one can use to influence transcriptional events in a predefined manner. One attractive strategy is the design or discovery of molecules that reconstitute the function of a natural transcription factor that can then be used to directly impact the transcriptional state of predefined genes. A second, related approach is to identify molecules that mimic one aspect of the structure of a particular transcription factor and in doing so serve as competitive inhibitors of important binding interactions. For both of these strategies, transcriptional activators of the amphipathic class have served as the inspiration, and molecules that reconstitute one or more of the functions of these complex transcription factors have been outstanding mechanistic tools with considerable therapeutic promise. As a visible and rapidly evolving field, progress in this area is frequently reviewed (3-8). In this minireview, we focus on four examples of activator⅐target protein complexes to highlight recent successes as well as the significant challenges remaining in the field.

In vivo modulation of hypoxia-inducible signaling by topographical helix mimetics

“…The transcription factorcoactivator interaction presents an intriguing target for controlling hypoxia signaling because it is a critical node directing downstream expression of various genes that work in concert to modulate cancer progression. From a ligand design perspective, transcriptional PPIs are often challenging because of their transient existence and relatively low binding affinities (26)(27)(28). Our work supports the hypothesis that topographical mimics of energetically important residues on protein secondary structures offer a rational approach for discovery of PPI inhibitors (3, 4, 8-11, 29, 30).…”

Transient-state Kinetic Analysis of Transcriptional Activator·DNA Complexes Interacting with a Key Coactivator

“…These values are in the range of diffusion-controlled processes (10 6 -10 7 M Ϫ1 s Ϫ1 ) (35), suggesting that this step is the binding of Med15 to the activator⅐DNA complex. 4 The observed rates for the slower phase (k obs,2 ) (Fig. 4b) were dependent on the identity of the TAD (Fig.…”

“…The unique transcriptional signatures associated with human disease have spurred enormous efforts toward the discovery of artificial transcriptional regulators (1)(2)(3)(4). These efforts are hampered by an incomplete understanding of the mechanism used by transcriptional activators to interact with and recruit the transcriptional machinery to a gene promoter (Fig.…”

Prepaying the entropic cost for allosteric regulation in KIX

“…Contained within CBP is an 87-residue-long domain called kinase-inducible domain interacting (KIX) that is critical for regulating transcriptional activity (for review, see ref. 11) and can be cooperatively targeted by a diverse set of transcription factors (12)(13)(14)(15)(16)(17) and small molecules (18)(19)(20)(21)(22)(23). The structure of KIX ( Fig.…”