Cdc37 as a Co-chaperone to Hsp90 - The Networking of Chaperones by Co-chaperones - page 103

Introduction
Folding of many proteins in the cell to a fully functional conformation requires
the influence of molecular chaperones (Ellis 2007 ). Such molecules appear to be
required to inhibit the formation of alternatively folded conformations that lack ca-
nonical gene function, and permit the majority of the translated protein to assume its
functional shape. It is now accepted by many that molecular chaperones play essen-
tial roles in cellular pathology as well as in normal function and roles for chaperone
overexpression in tumorigenesis and tumor progression have been described while
failure in chaperone function may underlie processes in aging (Calderwood et al.
2009 ; Ciocca et al. 2013 ; Ciocca and Calderwood 2005 ; Jinwal et al. 2012 ). The un-
derlying causes of increased chaperone expression in cancer and loss of chaperone
activity in aging have not currently been deduced. It has been assumed that elevated
amounts of proteins with or without oncogenic mutations accumulate in cancer in-
creasing the “folding burden placed on cancer cells (Calderwood and Gong 2012 ).
However direct proof for such a hypothesis is required. It is known that chaperones
such as Hsp27, Hsp70 and Hsp90 often undergo enhanced expression during cancer
development and play roles in many of the key steps in cancer development such
as acquisition of independent growth, escape from oncogene mediated programmed
cell death and senescence, de novo angiogenesis invasion and metastasis (Calder-
wood et al. 2006 ; Ciocca and Calderwood 2005 ). This may point to key regulatory
roles for the chaperones in cancer. In addition Hsp27, Hsp70 and Hsp90 are all
regulated at the transcriptional level primarily by heat shock factor 1 (HSF1) a pro-
tein that responds to both stress and cancer signals, leading to potent HSP synthesis
and enhanced tumorigenesis (Ciocca et al. 2013 ; Santagata et al. 2011 ). Interactions
between HSF1 and Hsp90 are particularly intriguing, as transcriptional activation of
HSF1 leads to Hsp90 increases, while Hsp90 is a potent HSF1 repressor, a tautol-
ogy with some significance in cellular responses to Hsp90 targeting drugs (Boell-
mann et al. 2004 ; Zou et al. 1998 ). Many members of the molecular chaperone
family require accessory proteins known as co-chaperones in order to function at
significant rates in cells (Calderwood 2013 ). Co-chaperones may be decisive in the
selection of Hsp90 clients within the cell and may determine the rate of polypeptide
folding and the ability of chaperones to stably interact with unstable proteins (Cox
and Johnson 2011 ). Optimal Hsp90 activity involves a wide range of co-chaperones
including Sgt1, p23, Aha1, Cdc37, Hop, Cyp40, FKBP1, FKBP2, PP5 phosphatase,
TTC4, TTC5 and XAP2 which regulate the chaperoning cycle as well as function
and localization in the cells (Calderwood 2013 ; Cox and Johnson 2011 ). The subject
of the current review is the Hsp90 co-chaperone role of Cdc37.
As would be surmised from its name, the CDC37 gene was discovered in a
screen for cell division cycle genes in S. cereviseae (Reed 1980 ). It has since been
shown to be conserved to man, although Cdc37 homologs in plants have not been
reported. Despite its discovery in a cell cycle screen, the Cdc37 protein apparently
does not perform a traditional cell cycle checkpoint role, such as has been attributed
to the cyclins and cell division kinases (cdk), and instead appears to function largely