Knock Down of Heat Shock Protein 27 (HspB1) Induces Degradation of Several Putative Client Proteins

Hsp27 belongs to the heat shock protein family and displays chaperone properties in stress conditions by holding unfolded polypeptides, hence avoiding their inclination to aggregate. Hsp27 is often referenced as an anti-cancer therapeutic target, but apart from its well-described ability to interfere with different stresses and apoptotic processes, its role in non-stressed conditions is still not well defined. In the present study we report that three polypeptides (histone deacetylase HDAC6, transcription factor STAT2 and procaspase-3) were degraded in human cancerous cells displaying genetically decreased levels of Hsp27. In addition, these proteins interacted with Hsp27 complexes of different native size. Altogether, these findings suggest that HDAC6, STAT2 and procaspase-3 are client proteins of Hsp27. Hence, in non stressed cancerous cells, the structural organization of Hsp27 appears to be a key parameter in the regulation by this chaperone of the level of specific polypeptides through client-chaperone type of interactions

Data from Hsp27 Modulates p53 Signaling and Suppresses Cellular Senescence

&lt;div&gt;Abstract&lt;p&gt;The small heat shock protein Hsp27 is expressed at high levels in many tumors and provides protection against anticancer drugs. Here, we show that expression of recombinant Hsp27 at elevated levels leads to protection of MCF10A human mammary epithelial cells from doxorubicin. The protection was associated with suppression of the doxorubicin-induced senescence, where Hsp27 inhibited p53-mediated induction of p21, the major regulator of the senescence program. Similarly, Hsp27 inhibited accumulation of p21 and suppressed senescence in response to the p53 activator nutlin-3, indicating that Hsp27 has a general effect on the p53 pathway. In line with these findings, down-regulation of Hsp27 in HCT116 human colon carcinoma cells that express this heat shock protein at high levels caused senescence in a population of cells and sensitized the rest of the cells to doxorubicin-induced senescence (at low doses) or apoptosis (at high doses of doxorubicin). Induction of senescence by Hsp27 down-regulation associated with activation of the p53 pathway and induction of p21. Interestingly, depletion of Hsp27 caused neither significant proteotoxic nor genotoxic stress, and therefore this heat shock protein seems to have a specific effect on the p53 signaling. Indeed, Hsp27 down-regulation was associated with destabilization of HDM2 and stabilization of p53. These data suggest that Hsp27 may play a general role in regulation of cellular senescence by modulating the p53 pathway. [Cancer Res 2007;67(24):11779–88]&lt;/p&gt;&lt;/div&gt;</jats:p

Supplementary Figure 3 from Hsp27 Modulates p53 Signaling and Suppresses Cellular Senescence

Supplementary Figure 3 from Hsp27 Modulates p53 Signaling and Suppresses Cellular Senescence</jats:p

Supplementary Figure 5 from Hsp27 Modulates p53 Signaling and Suppresses Cellular Senescence

Supplementary Figure 5 from Hsp27 Modulates p53 Signaling and Suppresses Cellular Senescence</jats:p

Supplementary Figure 4 from Hsp27 Modulates p53 Signaling and Suppresses Cellular Senescence

Supplementary Figure 4 from Hsp27 Modulates p53 Signaling and Suppresses Cellular Senescence</jats:p

Supplementary Figure 1 from Hsp27 Modulates p53 Signaling and Suppresses Cellular Senescence

Supplementary Figure 1 from Hsp27 Modulates p53 Signaling and Suppresses Cellular Senescence</jats:p

Supplementary Figure 3 from Hsp27 Modulates p53 Signaling and Suppresses Cellular Senescence

Supplementary Figure 3 from Hsp27 Modulates p53 Signaling and Suppresses Cellular Senescence</jats:p

Supplementary Figure 1 from Hsp27 Modulates p53 Signaling and Suppresses Cellular Senescence

Supplementary Figure 1 from Hsp27 Modulates p53 Signaling and Suppresses Cellular Senescence</jats:p

Supplementary Figure 5 from Hsp27 Modulates p53 Signaling and Suppresses Cellular Senescence

Supplementary Figure 5 from Hsp27 Modulates p53 Signaling and Suppresses Cellular Senescence</jats:p