Visit our Expo - Redox and Inflammation signaling 2012

Session X : Cell death in cancer Poster X, 15
hGTSE-1 protein can modulate the cellular response to stress by regulating the stability
of the cyclin-dependent kinase inhibitor p21CIP1/WAF1
Bublik DR, Scolz M, Monte M and Schneider C.
Human GTSE-1 (G2 and S phase-expressed-1) is a cell cycle-regulated protein with increased
expression during S and G2 phases of the cell cycle. We have previously demonstrated that
hGTSE-1 can negatively regulate p53 transactivation function, protein levels and p53dependent
apoptosis during the S/G2 cell cycle window. More recently we have observed
that, although hGTSE-1 represses p53 activity, it’s able to stabilize the cyclin-dependent
kinase inhibitor p21CIP1/WAF1. p21CIP1/WAF1 protein was shown to be strongly
regulated by hGTSE-1: p21CIP1/WAF1 levels were increased in cells with Ponasterone Ainducible
expression of hGTSE-1, and concomitantly downregulated in hGTSE-1-knocked
down cells, in a proteasome-dependent manner. As a functional consequence,
p21CIP1/WAF1 stabilization observed in hGTSE-1-induced cells, conferred resistance to
taxol-induced apoptosis; conversely, loss of p21CIP1/WAF1 after hGTSE-1 knock-down by
small interference RNA sensitized cells to taxol-induced apoptosis.
Besides, we have also found out that hGTSE-1-dependent stabilization of p21CIP1/WAF1
requires a functional Heat Shock Protein 90 (Hsp90) given that the specific Hsp90 inhibitor
Geldanamycin completely prevented hGTSE-1’s effects on p21CIP1/WAF1. We propose the
recently discovered Hsp90-binding and p21CIP1/WAF1-interactor TPR protein WISp39, as a
mediator that acts downstream of hGTSE-1 in regulating p21CIP1/WAF1 stability; indeed in
the absence of WISp39 hGTSE-1 failed to induce p21CIP1/WAF1 accumulation. Moreover,
a direct interaction between hGTSE-1, p21CIP1/WAF1 and WISp39 was confirmed in vitro
and in vivo suggesting that hGTSE-1 might be associated to the multi-protein Hsp90
chaperone complex.
These findings may support an important role of hGTSE-1 in maintaining and tightly
regulating p21CIP1/WAF1 levels thereby modulating its functions, and indicate that hGTSE-
1 could fine tune the cellular response to stress through regulation of p21CIP1/WAF1
turnover.
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