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).

Figure 1

Association of cahperones (HSPs) with cell cycle control proteins. Cdk, cyclin‐dependent kinase; Cdc25, cell division protein 25(phosphatase); Cdc37, cell division cycle protein 37, with similar function to HSP90; E2F/DP, heterodimer of transcription factor; INK4, p21Waf1 and p27Kip1, inhibitors of Cdks; p53, tumour suppressor; pRb, retinoblastoma protein (tumour suppressor); TGFß, transforming growth factor ß. Weel, inhibitory kinase. Heat shock proteins (HSPs), grey; →, activation; ⊣ inhibition (for further explanation see text).

Figure 2

Association of cahperones (HSPs) with proteins of the mitogen‐activated signal cascade. ERK, extracellular signal regulated kinases (also called mitogen‐activated protein (MAP) kinases); Grb, growth factor receptor‐bound protein, adaptor protein; MEK; ERK (MAPK) kinase; Mos, Raf ERK (MAPK) kinase kinase; Ras, derived from rat sarcoma, activator of Raf; RTK‐receptor tyrosine kinses; Sos ‘son of sevenless’, guanine nucleotide releasing protein; Src, derived from Rous sarcoma, non receptor tyrosine kinas; c‐Jun, c‐Fos, Elk1, SAP1,2, ATF2, cMyc, transcription factors. PLA2, Phospholipase A2; RSK, ribosomal S6 kinase. Heat shock proteins, grey (for further explanation see text).