Chaperoning signaling pathways

The role of heat shock proteins (HSPs) in protein folding, transport and complex formation has been studied extensively (Bukau and Horwich, 1998; Hartl, 1996). Their roles in signal transduction have been established from observations that Hsp90 and Hsp70 are associated with a number of signaling molecules, including v-Src, Raf1, Akt and steroid receptors (Dittmar et al., 1998; Sato et al., 2000; Xu and Lindquist, 1993). Decreasing the levels of functional Hsp90 in Drosophila by genetic mutation or by treatment with an Hsp90 inhibitor geldanamycin causes developmental abnormalities (Rutherford and Lindquist, 1998). Likewise, increasing the levels of Hsp70, by gene transfer mediated overexpression or by heat shock, has growth-inhibitory effects on mammalian tissue culture cells and in Drosophila salivary gland cells, whereas expression of a dominant-negative form of Hsp70 causes developmental defects in Drosophila (Elefant and Palter, 1999; Feder et al., 1992). However, what remains less well understood is whether this is a general strategy used by the cell to link specific signaling pathways with cell-stress-sensing events. Interestingly, cells that have lost their ability to regulate cell growth, such as tumor cells, often express high levels of multiple HSPs compared with their normal parental cells (Jaattela, 1999). Depletion of Hsp90 by geldanamycin or of Hsp70 by anti-sense methodology in transformed cells, but not in their non-transformed counterparts, causes either arrest of cell growth or cell death (Nylandsted et al., 2000; Whitesell et al., 1994). Tumor cells appear to be dependent on increased levels of HSPs, although why this is beneficial has yet to be clearly established. One possibility is the ability of chaperones to suppress and buffer mutations that accumulate during the transformation process, which could promote cell viability and even enhanced cell growth of otherwise mutant cells. This is exemplified by the relationship between p53, Hsp70 and Hsp90, where mutant forms of p53, but not wild-type p53, depend on Hsp70 and Hsp90 for normal level and function (Blagosklonny et al., 1996; Pinhasi-Kimhi et al., 1986).