Previous posts have attempted to demonstrate that there is a potential role for (Heat Shock) proteins that mask mutations, to enable rapid evolutionary changes. The Hsp90 protein has been presented and the basic problems one face to explain bursts in evolution have been outlined. Now the time has come to show real examples of Hsp90 influencing the evolution of traits.

The following are very short summaries of key papers. For details, please see the referenced papers.

1. Hsp90 and Cancer

In 1993 Yang Xu and Susan Lindquist showed that Hsp90 associates with v-src and inhibits its activity in an concentration-dependent manner. Hsp90 was not merely an on and off switch for v-src, but exhibited transient inhibition, dependent on intracellular concentration of Hsp90. This was a clue to understanding Hsp90’s role in cancer (as well as in evolution). After this, many cancer-related proteins have been identified that interact with Hsp90 (see table).

Table from a review in Nature 2005 by Whitesell and Lindquist

The mechanism one speculates, is similar at the molecular level, to the mechanisms postulated for morphological change. Hsp90 stabilizes the otherwise unstable oncogenic proteins, to aid in tumor growth in an environment hostile to tumor development. In other words: the heat shock proteins protects the oncogenic cells from stress. When the tumor cells subsequently attain further mutations and protein alterations, inherent to oncogenic growth, the heat shock proteins are unable to stabilize all of the altered proteins and the tumor can progress into accelerated growth and/or metastasis. The role of Hsp90 in cancer development has been widely accepted and inhibitors of Hsp90 activity is currently undergoing clinical trials for cancer treatments.

2. Drosophila

The key paper on Hsp90 and Drosophila evolution is the Rutherford and Lindquist paper in Nature 1998. This paper has been mentioned on several previous posts here on SciPhu and also in the introductory Just Science post. Again, the take home message is that reducing levels of Hsp90-activity leads to changes in phenotype. The reason for such dramatic effects is probably that Hsp90 stabilizes proteins that are key elements in intracellular signaling pathways. Often these are kinases, phosphatases or transcription factors, see this table for full list. The common feature of these affected proteins is that they regulate the activity of other proteins downstream in the signaling cascade. Thus, changes in the activity of one master protein acts on the stability and function of many other “executive” proteins ultimately resulting in massive changes. The phenomenon has further been elucidated in other species……….

3. Yeast

In yeast, a reduction in Hsp90 levels potentiates drug resistance and this resistance has multigenic determinants working through Hsp90. Hsp90 thus helps yeast evolve to counter the stressful effect of the drug. Interestingly, this effect is diminished by temperature rise. Increasing the stress (by adding heat) therefore, titrates Hsp90 away from the drug-resistance and makes the yeast vulnerable again (could this effect explain why fever has developed ?).

4. Arabidopsis

Evidence for the same mechanisms occurring in plants comes mainly from two publications on Arabidopsis thaliana (Queitsch C et al. and Sangster TA et al.). These images from the latter publication show the extensive morphological changes seen in the plants.

Figure 2. Similar morphological phenotypes of seedlings with reduced HSP90 function by RNAi or pharmacological means (GDA). (a) and (b): purple pigment accumulation; (c) and (d): organ number defect; (e) and (f): narrowly-shaped deformed true leaves; (g) and (h): twisted rosettes; (i) and (j): lobed cotyledon. RNAi plants are T₃ generation with from line RNAi-A3. Size bar 2 mm for b and g–i, 1 mm for a, c–f, and 3 mm for normal phenotype. (b) and (f) originally published in [5].

These effects can also be induced by increasing the temperature. Demonstrating the generality in the stress response. Since the genetics of these plants is easier to trace in these plants than in Drosophila or Yeast, the evidence for buffering genetic changes is even more clear-cut in this organism.

An excellent illustration to summarize Hsp90-buffering comes from Sangster TA et al.:

In the last post I will present published models on how Hsp90 can act in evolution, – welcome back for the last post in Just Science 08, tomorrow.