Breast cancer cell invasion mediated by Gα12 signaling involves expression of interleukins-6 and -8, and matrix metalloproteinase-2.

BACKGROUND: Recent studies on the involvement of the G12 family of heterotrimeric G proteins (Gα12 and Gα13, the products of the GNA12 and GNA13 genes, respectively) in oncogenic pathways have uncovered a link between G12 signaling and cancer progression. However, despite a well characterized role of Rho GTPases, the potential role of secreted factors in the capacity of G12 signaling to promote invasion of cancer cells is just beginning to be addressed. METHODS: MDA-MB-231 and MCF10A breast cancer cell lines were employed as a model system to explore the involvement of secreted factors in G12-stimulated cell invasion. Factors secreted by cells expressing dominant-active Gα12 were identified by protein array, and their involvement in breast cancer cell invasion was assessed through both RNAi-mediated knockdown and antibody neutralization approaches. Bioinformatics analysis of the promoter elements of the identified factors suggested NF-κB elements played a role in their enhanced expression, which was tested by chromatin immunoprecipitation. RESULTS: We found that signaling through the Gα12 in MDA-MB-231 and MCF10A breast cancer cell lines enhances expression of interleukins (IL)-6 and -8, and matrix metalloproteinase (MMP)-2, and that these secreted factors play a role in G12-stimulated cell invasion. Furthermore, the enhanced expression of these secreted factors was found to be facilitated by the activation of their corresponding promoters, where NF-κB seems to be one of the major regulators. Inhibition of IL-6 and IL-8, or MMP-2 activity significantly decreased Gα12-mediated cell invasion. CONCLUSIONS: These studies confirm and extend findings that secreted factors contribute to the oncogenic potential of G12 signaling, and suggest potential therapeutic targets to control this process.

Gαz regulates BDNF-induction of axon growth in cortical neurons.

The disruption of neurotransmitter and neurotrophic factor signaling in the central nervous system (CNS) is implicated as the root cause of neuropsychiatric disorders, including schizophrenia, epilepsy, chronic pain, and depression. Therefore, identifying the underlying molecular mechanisms by which neurotransmitter and neurotrophic factor signaling regulates neuronal survival or growth may facilitate identification of more effective therapies for these disorders. Previously, our lab found that the heterotrimeric G protein, Gz, mediates crosstalk between G protein-coupled receptors and neurotrophin signaling in the neural cell line PC12. These data, combined with Gαz expression profiles--predominantly in neuronal cells with higher expression levels corresponding to developmental times of target tissue innervation--suggested that Gαz may play an important role in neurotrophin signaling and neuronal development. Here, we provide evidence in cortical neurons, both manipulated ex vivo and those cultured from Gz knockout mice, that Gαz is localized to axonal growth cones and plays a significant role in the development of axons of cortical neurons in the CNS. Our findings indicate that Gαz inhibits BDNF-stimulated axon growth in cortical neurons, establishing an endogenous role for Gαz in regulating neurotrophin signaling in the CNS.

Notch as a molecular switch in neural stem cells.

Notch signaling pathway, originally discovered in Drosophila, impinges on a wide array of cellular processes including cell proliferation, cell differentiation, and cell apoptosis. Recent accumulating evidences implicated the important roles of Notch signal pathway in different aspects of stem cell biology of neural stem cell (NSC). In vivo and in vitro studies illustrated that Notch signal pathway could promote gliogenesis, inhibit premature neurogenesis, and be involved in self-renew of NSC. This short review summarizes the roles of the Notch signaling pathway on gliogenesis, neurogenesis, and self-renew of NSC and their underlying molecular mechanisms.

Cardiovascular dementia - a different perspective.

The number of dementia patients has been growing in recent years and dementia represents a significant threat to aging people all over the world. Recent research has shown that the number of people affected by Alzheimer's disease (AD) and dementia is growing at an epidemic pace. The rapidly increasing financial and personal costs will affect the world's economies, health care systems, and many families. Researchers are now exploring a possible connection among AD, vascular dementia (VD), diabetes mellitus (type 2, T2DM) and cardiovascular diseases (CD). This correlation may be due to a strong association of cardiovascular risk factors with AD and VD, suggesting that these diseases share some biologic pathways. Since heart failure is associated with an increased risk of AD and VD, keeping the heart healthy may prove to keep the brain healthy as well. The risk for dementia is especially high when diabetes mellitus is comorbid with severe systolic hypertension or heart disease. In addition, the degree of coronary artery disease (CAD) is independently associated with cardinal neuropathological lesions of AD. Thus, the contribution of T2DM and CD to AD and VD implies that cardiovascular therapies may prove useful in preventing AD and dementia.

Leucine-rich repeat kinase 2-linked Parkinson's disease: clinical and molecular findings.

Mutations in Leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of sporadic and familial late onset Parkinson's disease (PD). The G2019S common mutation has been identified about 1% of sporadic cases and 4-7% of familial cases. Over 50 variants have since been identified in LRRK2, and at least 7 of these are confirmed to be pathogenic. In addition to pathogenic mutations, several common polymorphisms in the LRRK2 gene (G2385R and R1628P) have been identified that may explain up to 10% of sporadic PD in Asian populations. LRRK2 is a large complex multidomain protein with 2,527-amino-acid and the molecular weight is 286 kDa. LRRK2 multidomain protein consists of a catalytic core domain, kinase domain and a number of putative protein-protein interaction domains. LRRK2 mutations found in PD families, including the G2019S and I2020T mutations show increased intrinsic kinase activity, when assessed with myelin basic protein as substrate. The modification of LRRK2 GTPase and kinase activity affecting residues in the ROC, COR and mitogen-activated protein kinase kinase kinases domains is believed to lead to neuronal cell death, but the pathways involved remain unclear. A number of in vivo models in C. elegans, D. melanogaster and mice have been developed to study the patho/physiological function of LRRK2. Based on current literature, a toxic gain of function in LRRK2 kinase activity is a possible pathophysiologic mechanism and thus inhibition of kinase activity in experimental models offers a potential therapeutic strategy for LRRK2-linked PD.

LRRK2 in Parkinson's disease: genetic and clinical studies from patients.

Mutations in leucine-rich repeat kinase 2 (LRRK2) (PARK8) are associated with both familial and sporadic forms of Parkinson's disease. Most studies have shown that LRRK2 mutations may explain between 5% and 13% of familial and 1-5% of sporadic Parkinson's disease. Importantly, a common recurrent mutation (G2019S) located in the kinase domain has been reported across most ethnic populations, with the highest prevalence among Ashkenazi Jews and North African Arabs. A recent worldwide meta-analysis pooling data from 24 populations reported a higher occurrence of G2019S in southern than in northern European countries and the penetrance is estimated to be approximately 75% at the age of 79 years. The R1441 'hotspot' amino acid codon residue (G/H/C) in the Ras of complex proteins domain is the second most common site of pathogenic LRRK2 substitutions after G2019S, with most carriers developing symptoms by the age of 75 years. Two polymorphic variants found almost exclusively among Asians (G2385R and R1628P) have been shown to increase the Parkinson's disease risk by approximately two-fold. The mutational event associated with R1628P is more recent, occurring approximately 2500 years ago, compared to estimates of 4000 years for G2385R carriers. LRRK2 mutation carriers generally simulate late onset Parkinson's disease and present with the usual typical clinical features. Genetic testing for G2019S in sporadic late-onset Parkinson's disease can be considered in some situations and may be useful in populations with high carrier status. The identification of asymptomatic mutation and risk variant carriers provides a unique opportunity for recruiting these subjects in potential neuroprotective trials and longitudinal studies to identify biomarkers of neurodegeneration.