Hsp90, the concertmaster: tuning transcription

Abstract

In the last decade, Hsp90 has emerged as a major regulator of cancer cell growth and proliferation. In cancer cells, it assists in giving maturation to oncogenic proteins including several kinases and transcription factors (TF). Recent studies have shown that apart from its chaperone activity, it also imparts regulation of transcription machinery and thereby alters the cellular physiology. Hsp90 and its co-chaperones modulate transcription at least at three different levels. In the first place, they alter the steady-state levels of certain TFs in response to various physiological cues. Second, they modulate the activity of certain epigenetic modifiers, such as histone deacetylases or DNA methyl transferases, and thereby respond to the change in the environment. Third, they participate in the eviction of histones from the promoter region of certain genes and thereby turn on gene expression. In this review, we discuss the role of Hsp90 in all the three aforementioned mechanisms of transcriptional control, taking examples from various model organisms with a special emphasis on cancer progression.

Keywords: Hsp90; cancer; chromatin modifiers; transcription; transcription factors.

Figure 1

Schematic representation of direct and in-direct roles of Hsp90 in transcription. (1) Hsp90 and its co-chaperones aid in the folding of various transcription factors either activators or repressors. (2) It also assists their nuclear transport. (3) Hsp90 being present at the TSS regulates transcription either by nucleosome removal or by stalling RNA polymerase II. Removal of Hsp90 complex thereby allows the movement of RNA polymerase II and initiates gene transcription. (4) Hsp90 aids in the maturation and enhances the activity of several chromatin modifiers. However, it is not clear whether it assists their entry into the nucleus. (5 and 6) Chromatin modifiers upon maturation by Hsp90 are responsible for maintaining euchromatin or heterochromatin states under various conditions. Hsp90 remains associated with some chromatin modifiers (e.g., Trx) near actively transcribing gene.