Abstract
ABSTRACTSurvivin expression is pivotal to life and death at the cellular level. For the past decade its pro-survival activity has been attributed to its essential role in cell proliferation and its ability to inhibit apoptosis. However, a growing body of evidence suggests that it may also contribute to cell viability through an as yet undefined role in autophagy. We report that survivin overexpression in osteosarcoma (U2OS) cells is associated with increased LC3-II expression, smaller autophagosomes, enlarged lysosomes and reduced autophagic flux. We also demonstrate that survivin binds LC3 directly through a canonical LC3-interacting region (LIR) in its baculovirus inhibitors of apoptosis protein (IAP) repeat BIR domain, mutation of which inhibits the interaction, but does not abrogate its influence on autophagy. Collectively these data suggest that survivin expression restricts autophagic flux, thereby inhibiting late-stage autophagy and preventing cell death, but does so independently of LC3.
Highlights
Implicit in its name survivin is a protein that promotes cell survival
Using live fluorescence imaging, immunoblotting and immunoprecipitation assays, here we report that overexpression of survivin increases LC3-II levels, reduces autophagosome size, enlarges lysosomes, and causes an overall reduction in autophagic flux
When survivin is overexpressed in cancer it is hugely detrimental to human health: its abundance correlates with tumour resistance to radiation, and this is recapitulated in cell culture (Colnaghi et al, 2006; Connell et al, 2008; Chakravarti et al, 2004)
Summary
Implicit in its name survivin is a protein that promotes cell survival. It is overexpressed in cancer (Ambrosini et al, 1997) where its presence correlates with increased resistance to chemotherapy (Paik et al, 2004) and irradiation (Colnaghi et al, 2006), treatments aimed at killing cancer cells. Its expression is a biomarker of poor patient prognosis and survivin itself is a promising target for cancer therapy Survivin is both essential for mitosis and can suppress cell death (Altieri, 2008; Wheatley and McNeish, 2005). In terms of apoptotic inhibition, several models have been suggested, including inhibition of the mitochondrial apoptosis promoting factor Smac/DIABLO (Pavlyukov et al, 2011; Song et al, 2003); stabilization of X-linked inhibitor of pro-apoptotic protein (XIAP) (Dohi et al, 2004); and induction of the mitochondrial-nuclear translocation of apoptosis inducing factor (Ambrosini et al, 1997). In addition to its roles in mitosis and apoptosis, we show that survivin can act in a pro-survival manner by preventing excessive autophagy, but it does so independently of its interaction with LC3
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