semagacestat br Experimental section br Acknowledgements br

Experimental section
Acknowledgements
Introduction DJ-1 is a highly conserved, homodimeric protein that was originally cloned as an oncogene capable of transforming semagacestat in cooperation with activated ras[1]. DJ-1 is over-expressed in multiple tumor types and is positively correlated with tumor metastasis and negatively correlated with patient survival [2], [3], [4], [5], [6], [7], [8]. Knockdown of DJ-1 sensitizes various tumor cell types to chemotherapeutic drugs [7], demonstrating its crucial role in tumor maintenance. Increased levels of DJ-1 in serum and extracellular fluids have also been proposed as a predictive biomarker in some cancers [9], [10] highlighting its potential for cancer diagnosis and prognosis. While over-expression of DJ-1 in somatic cell lines appears to mediate cancer development, loss of function mutations of DJ-1 in post-mitotic neurons are linked to recessively inherited Parkinson's disease characterized by neuodegeneration of substantia nigra dopaminergic neurons [11]. This places DJ-1 at the center of a nuanced balance where it can regulate cellular processes depending on cell type and serves as a determinant of cell survival or cell death in response to extracellular stimuli. One way that DJ-1 appears to control cellular homeostasis is through its ability to modulate signal transduction - cell signaling pathways which are able to convey, amplify, and translate the information transmitted from the plasma membrane to the nucleus. For example, DJ-1 can activate the extracellular signal-regulated kinase (ERK1/2) pathway [12], [13] and the phosphatidylinositol-3-kinase (PI3K)/Akt pathway [8] to mediate cell survival and proliferation. It can attenuate cell death signaling by inhibiting apoptosis signal-regulating kinase 1 (ASK1) activation [14], [15] as well as the mitogen-activated protein kinase kinase kinase 1 (MEKK1/MAP3K1) activation [16] of downstream apoptotic cascades. It also modulates autophagy through many signaling pathways [17], [18], [19], a process that can mediate either cell survival or cell death depending on the circumstances [20]. The direct neuroprotective effects of DJ-1 have long been attributed to cysteine residues that sense and attenuate oxidative stress. Its three cysteine residues at Cys46, Cys56, and Cys106 are thought to scavenge reactive oxygen species (ROS) with the quenching activity of their sulfhydryl groups, thereby reducing cellular ROS burden [21]. Cys106, the critical residue considered most susceptible to oxidation, is oxidized to cysteine sulfenic acid (Cys-SOH), cysteine sulfinic acid (Cys-SO2H), and then cysteine sulfonic acid (Cys-SO3H) forms, causing the isoelectric point (pI) to shift towards more acidic values. Excessively oxidized Cys106-SO3H form of DJ-1 is considered inactive, and mutation of Cys106 results in loss of neuroprotective function [22]. The anti-oxidant activity of DJ-1 is demonstrated by its ability to protect neurons against toxins that increase cellular ROS levels, including H2O2, 6-OHDA, rotenone and MPTP, in various in vitro and in vivo studies [18], [23], [24], [25]. Conversely, knocking down DJ-1 exacerbates the cell death induced by oxidative stress [25], [26], [27], [28], [29]. Investigating the function of DJ-1 in cell signaling has been helpful in understanding its function in maintaining cellular homeostasis, and its contrasting roles in neurodegeneration and cancer [30], [31]. In this review, we focus on the extracellular signal-regulated kinase (ERK1/2) pathway and the Daxx-apoptosis signal-regulating kinase 1 (ASK1) death signaling pathway as they relate to the anti-oxidant activity of DJ-1.
Conclusion DJ-1 has emerged as a significant player in major signaling pathways such as ERK1/2 and ASK1, with distinct effects in cancer pathogenesis and neuronal survival. Under oxidative stress, DJ-1 activates the ERK1/2 pathway, which controls the balance of cell proliferation and growth. DJ-1 also inhibits the ASK1 pathway, which plays a key role in stress-induced apoptosis, with overall effects being protection from oxidative injury. However, the majority of studies utilize simple cellular models looking at the effects of various stresses and stimuli. Much of these data need to be confirmed in in vivo models where complex cross-talk between various signaling pathways may modulate the overall effects of DJ-1. Nevertheless, a large body of data indicates that DJ-1 impacts the signaling processes that maintain cellular homeostasis under oxidant stress, as well as the delicate balance between premature cell death and uncontrolled proliferation. This suggests the importance of understanding the role of DJ-1 in regulating signal transduction and developing strategies to target it for therapeutic interventions in neurodegeneration and cancer.