Chaperones in cell cycle regulation and mitogenic signal transduction: a review

Abstract

Chaperones/heat shock proteins (HSPs) of the HSP90 and HSP70 families show elevated levels in proliferating mammalian cells and a cell cycle-dependent expression. They transiently associate with key molecules of the cell cycle control system such as Cdk4, Wee-1, pRb, p53, p27/Kip1 and are involved in the nuclear localization of regulatory proteins. They also associate with viral oncoproteins such as SV40 super T, large T and small t antigen, polyoma large and middle S antigen and EpsteinBarr virus nuclear antigen. This association is based on a J-domain in the viral proteins and may assist their targeting to the pRb/E2F complex. Small HSPs and their state of phosphorylation and oligomerization also seem to be involved in proliferation and differentiation. Chaperones/HSPs thus play important roles within cell cycle processes. Their exact functioning, however, is still a matter of discussion. HSP90 in particular, but also HSP70 and other chaperones associate with proteins of the mitogen-activated signal cascade, particularly with the Src kinase, with tyrosine receptor kinases, with Raf and the MAP-kinase activating kinase (MEK). This apparently serves the folding and translocation of these proteins, but possibly also the formation of large immobilized complexes of signal transducing molecules (scaffolding function).

Identification of differentially expressed proteins in human glioblastoma cell lines and tumors

“…3B, top). The observed locations of these spots on 2D gels were consistent with literature evidence that posttranslational modifications of Hsp27 have Isoelectric point (pI) values from 5 to 7 (Helmbrecht et al, 2000). The spots c and e were subsequently shown to be nonphosphorylated 205 and 199 amino acid isoforms of Hsp27, respectively, whereas spots b and d were identified as respective isoforms with one phosphate group on Ser82 (Fig.…”

Mathematical modeling of heat shock protein synthesis in response to temperature change

“…In light of our model's predictions and knowing that: (i) some cancer cells are more sensitive to hyperthermia then others, and (ii) elevated expression of Hsp70 and Hsp90 in tumour cells has been detected in several cases [6,7], we may question whether this hyperthermia sensitivity and elevated expression of heat shock proteins are not correlated i.e. whether cancer cells with overexpression of Hsp70 and Hsp90 are more resistant to hyperthermia than cancer cells without over-expression of Hsp70 and Hsp90.…”

“…3 shows the dynamics of Hsp70 mRNA resulting from a computational simulation of equations (1)(2)(3)(4)(5)(6)(7)(8)(9) where the temperature varies from 37 o C up to 42 o C in case of heat shock (solid line plot, corresponding to the temperature profile shown on Fig. 2 (A)), slow heating (dashed line plot, corresponding to the temperature profile shown on Fig.…”

“…1). Hsp70 translation rate 0.035 k 6 rate of HSF dissociation and formation of Hsp70 0.023 Substrate complexes l 6 rate of Substrate dissociation and formation of 0.00036 Hsp70 HSF compexes k 10 refolding rate 0.014 l 10 rate constant of Hsp70 degradation 0.013 k 8 translation rate 0.035 k 7 rate of active HSF HSE association 0.035 l 7 rate of active HSF HSE dissociation 0.035 Table 1: Estimated values of the model parameters. We note that the parameters have dimensions (Time) −1 (M) −n+1 , where M is the (molar) concentration and n is the number of molecules formed in a complex.…”

“…in general cancer, and specifically solid tumors). Elevated expression of Hsp70 and Hsp90 in tumour cells has been detected in several cases [6,7]. In breast cancer, over-expression of Hsp70 has been correlated with metastasis and poor prognosis [5,8,20].…”