Although mutations in the parkin gene are frequently associated with familial Parkinsonism, emerging evidence suggests that parkin also plays a role in cancers as a putative tumor suppressor. Supporting this, we show here that parkin expression is dramatically reduced in several breast cancer-derived cell lines as well as in primary breast cancer tissues. Importantly, we found that ectopic parkin expression in parkin-deficient breast cancer cells mitigates their proliferation rate both in vitro and in vivo, as well as reduces the capacity of these cells to migrate. Cell cycle analysis revealed the arrestment of a significant percentage of parkin-expressing breast cancer cells at the G1-phase. However, we did not observe significant changes in the levels of the G1-associated cyclin D1 and E. On the other hand, the level of cyclin-dependent kinase 6 (CDK6) is dramatically and selectively elevated in parkin-expressing breast cancer cells, the extent of which correlates well with the expression of parkin. Interestingly, a recent study demonstrated that CDK6 restrains the proliferation of breast cancer cells. Taken together, our results support a negative role for parkin in tumorigenesis and provide a potential mechanism by which parkin exerts its suppressing effects on breast cancer cell proliferation.Mutations in the parkin gene, located on chromosome 6q25.2-27, are a predominant cause of inherited parkinsonism (1). Accordingly, much of the interest in characterizing the function of the parkin gene has been directed toward understanding its role in neurodegeneration. However, aberrant parkin function has also been linked to several other disorders (2, 3), among which, to the development of several types of cancers (4). Comparatively, the role of parkin in these disorders is less well characterized.Supporting a role for parkin in cancers, a previous study by Cesari et al. (4) involving physical mapping combined with loss of heterozygosity (LOH) 4 analysis identified the 6q-located, 1.4 Mb parkin as a gene that is frequently targeted by hemizygous deletion and inactivation in both malignant tumors and tumorderived cell lines. Following this discovery, several other groups have reported parkin gene alterations and expression variability in a variety of tumor biopsies and tumor cell lines representing a wide range of cancers including breast and ovarian cancers (4 -8). Frequently, diminished or absent parkin expression was observed in these cancers, suggesting that parkin may have tumor suppression properties. Consistent with this, microcellmediated transfer of human chromosome 6 suppresses tumorigenicity in several cancer cell lines (9), and introduction of an intact chromosome 6 into MCF7 (a breast cancer cell line) restores its ability to senesce (10). Collectively, these studies support the existence of a tumor suppressor gene (TSG) on chromosome 6q and the potential candidacy of parkin as a TSG. However, whether and how the loss of parkin function contributes to the development of cancers are currently not well...

Loss of parkin function is a predominant cause of familial Parkinsonism. Emerging evidence also suggests that parkin expression variability may confer a risk for sporadic Parkinson disease. We have recently demonstrated that a wide variety of Parkinson disease-linked stressors, including dopamine (DA), induce parkin solubility alterations and promote its aggregation within the cell, a phenomenon that may underlie the progressive susceptibility of the brain to degeneration. The vulnerability of parkin to stress-induced modification is likely due to its abundance of cysteine residues. Here, we performed a comprehensive mutational analysis and demonstrate that Cys residues residing both within and outside of the RING-IBR (in between RING fingers)-RING domain of parkin are important in maintaining its solubility. The majority of these Cys residues are highly conserved in parkin across different species and potentially fulfil important structural roles. Further, we found that both parkin and HHARI (human homologue of Drosophila ariadne), another RING-IBR-RING-type ubiquitin ligase, are comparably more susceptible to solubility alterations induced by oxidative and nitrosative stress when compared with other non-RING-IBR-RING Cys-containing enzymes. However, parkin appears to be uniquely sensitive to DA-mediated stress, the specificity of which is likely due to DA modification of 2 Cys residues on parkin (Cys-268 and Cys-323) that are distinct from other RING-IBR-RING members. Parkinson disease (PD)4 is the most common neurodegenerative movement disorder characterized pathologically by the rather selective loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the presence of intraneuronal protein inclusions known as Lewy bodies. Although most cases of PD occur in a sporadic manner, a subset of PD cases is inheritable and attributable to mutations in specific genes. These familial PD-linked genes include ␣-synuclein, parkin, DJ-1, PINK1, and LRRK2 (1, 2). Of these, mutations in the parkin gene are currently recognized to be a predominant cause of familial, early onset PD (3-5). Further, emerging evidence also suggests that parkin expression variability may confer a risk for the development of the more common, sporadic form of PD (6, 7).The importance of functional parkin to dopaminergic neuronal survival is probably related to the multitude of neuroprotective roles it serves (8, 9). Parkin functions as a ubiquitin ligase associated with protein homeostasis and apparently confers protection to neurons against a diverse range of cellular insults (8,9). Recently, we have demonstrated that a wide variety of PD-linked stressors, including dopamine (DA), induce parkin solubility alterations and promote its aggregation within the cell (10). Our observations corroborated with a similar study conducted by LaVoie et al. (11), who further showed that DA covalently modifies parkin via its Cys residues, although the number and location of the Cys targeted by DA remain unknown. Since parkin functions as a br...

Locus Chromosome Gene Inheritance Function PARK1 & 4 4q21-23 α-synuclein (SNCA) Dominant Unclear (presynaptic protein) PARK2 6q25.2-27 Parkin (PRKN) Recessive Ubiquitin ligase PARK3 2p13 Unknown Dominant-PARK5 4p14 UCHL1 Dominant Ubiquitin hydrolase PARK6 1p35-36 PINK1 Recessive Putative serine/threonine kinase PARK7 1p36 DJ-1 Recessive Redox sensor PARK8 12p11.2-q13.1 LRRK2/dardarin Dominant Putative serine/threonine kinase PARK9 1p36 ATP13A2 Recessive Lysosomal P-type ATPase PARK10 1p32 Unknown Unknown-PARK11 2q37.1 Unknown Dominant-PARK12 Xq21-q25 Unknown Unknown-PARK13 2p12 Omi/HtrA2 Dominant Mitochondrial serine protease PARK14 22q13.1 PLA2G6 Recessive Phosopholipase PARK15 22q12-q13 FBXO7 Recessive Component of SCF E3 complex PARK16 1q32 Unknown Unknown-Table 1. PD-linked genes www.intechopen.com