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1.  Connection between Tumor Suppressor BRCA1 and PTEN in Damaged DNA Repair 
Frontiers in Oncology  2014;4:318.
Genomic instability finally induces cell death or apoptosis. The tumor suppressor, phosphatase and tensin homolog on chromosome 10 (PTEN), is a dual-specificity phosphatase, which has protein phosphatase activity and lipid phosphatase activity that antagonizes PI3K activity. Cells that lack PTEN have constitutively higher levels of PIP3 and activated downstream PI3K/AKT targets. BRCA1, a well-known breast cancer tumor suppressor, is to associate with breast cancer risk and genetic susceptibility. Many studies have demonstrated that PTEN, as well as BRCA1, plays a critical role in DNA damage responses. The BRCA1 functionally cooperates with PTEN and might be an essential blockage in the development of several tumors. Actually, the PTEN and BRCA1 genes are recognized as one of the most frequently deleted and/or mutated in many human cancers. The PI3K/AKT pathway is constitutively active in BRCA1-defective human cancer cells. Loss or decrease of these PTEN or BRCA1 function, by either mutation or reduced expression, has a role in various tumor developments. This review summarizes recent findings of the function of BRCA1 and PTEN involved in genomic stability and cancer cell signaling.
PMCID: PMC4226230  PMID: 25426449
BRCA1; PTEN; genome stability; reactive oxygen species; DNA repair; cell signaling; carcinogenesis
2.  Certain Diet and Lifestyle May Contribute to Islet β-cells Protection in Type-2 Diabetes via the Modulation of Cellular PI3K/AKT Pathway 
PI3K/AKT pathway has been shown to play a pivotal role on islet β-cell protection, enhancing β-cell survival by stimulating cell proliferation and inhibiting cell apoptosis. Accordingly, this pathway appears to be crucial in type-2 diabetes. Understanding the regulations of this pathway may provide a better efficacy of new therapeutic approaches. In this review, we summarize advances on the involvement of the PI3K/AKT pathway in hypothetical intra-cellular signaling of islet β-cells. As recent findings may show the nutritional regulation of the survival pathway in the islet β-cells through activation of the PI3K/AKT pathway, we also review studies on the features of several diets, correlated lifestyle, and its signaling pathway involved in type-2 diabetes. The molecular mechanisms contributing to the disease are the subject of considerable investigation, as a better understanding of the pathogenesis will lead to novel therapies against a condition of the disease.
PMCID: PMC4231374  PMID: 25400709
AKT; GSK3β cell signaling; islet β-cells; type-2 diabetes; PI3K.
3.  Rip2 contributes to host defense against Anaplasma phagocytophilum infection 
The gram-negative obligate intracellular bacterium Anaplasma phagocytophilum is the causative agent of human granulocytic anaplasmosis (HGA), an emerging tick-borne infectious disease occuring worldwide. HGA is generally self-limiting, however, the underlying mechanisms, particularly the innate immune pathways that mediate the immune clearance of A. phagocytophilum, are less understood. We herein report an unexpected role for Receptor interacting protein-2 (Rip2), the adaptor protein for the Nod-Like Receptors (NLRs), Nod1/Nod2, in the host immune response against A. phagocytophilum infection. Although A. phagocytophilum genome is reported to lack the genes encoding the known ligands of Nod1 and Nod2, its infection up-regulated the transcription of Rip2 in human primary neutrophils. Our results revealed that Rip2 deficient mice had significantly higher bacterial load than wild type controls throughout the infection period. In addition, the Rip2 deficient mice took strikingly longer duration to clear A. phagocytophilum infection. Detailed analysis identified that interferon gamma (IFNγ) and interleukin -18 (IL-18) but not interleukin -12 (IL-12), macrophage inflammatory protein-2 (MIP-2), and KC response were diminished in A. phagocytophilum-challenged Rip2 deficient mice. Together, these results revealed that Rip2 play important roles in the immune control of A. phagocytophilum, and may contribute to our understanding of the host response to Rickettsiales.
PMCID: PMC3530031  PMID: 22747758
Rip2; Anaplasma phagocytophilum; NLR; IFNγ
4.  Crohn’s Disease-Associated Nod2 Mutation Limits Production of Pro-Inflammatory Cytokines to Protect the Host from Enterococcus faecalis-Induced Lethality1 
Nod2 mutations including L1007fsinsC are associated with the development of Crohn’s disease (CD). These CD-associated Nod2 mutations are common in healthy Caucasian populations, suggesting that they may confer some protective function, but experimental evidence is lacking. Using a mouse strain that expresses Nod22939iCstop, the equivalent of the L1007fsinsC mutation, we found that macrophages homozygous for Nod22939iCstop are impaired in the recognition of MDP and E. faecalis, a commensal bacterium that is a common cause of sepsis-associated lethality in humans. Notably, Nod2 deficiency and homozygocity for Nod22939iCstop were associated with reduced production of TNF-α and IL-6 and lethality after systemic infection with E. faecalis despite normal bacteria loads. Consistently, inhibition of TNF-α Signaling protected wild-type mice from E. faecalis-induced lethality. These results suggest that the same Nod2 mutation can increase the susceptibility to CD, but also protect the host from systemic infection by a common enteric bacterium.
PMCID: PMC3169738  PMID: 21849681
5.  Maturation Modulates Caspase-1 Independent Responses of Dendritic Cells to Anthrax Lethal Toxin 
Cellular microbiology  2008;10(5):1190-1207.
Anthrax lethal toxin (LT) contributes to the immune evasion strategy of B. anthracis by impairing the function of cells of the immune system, such as macrophages and dendritic cells (DCs). Macrophages from certain inbred mice strains undergo rapid death upon LT treatment mediated by caspase-1 activation dependent on Nalp1b, an inflammasome component. Rapid LT-induced death is however not observed in macrophages from human and many mouse strains. Here, we focused on the responses of various murine DCs to LT. Using a variety of knock-out mice, we found that depending on the mouse strain, death of bone marrow derived DCs and macrophages was mediated either by a fast Nalp1b and caspase-1 dependent, or by a slow caspase-1 independent pathway that was triggered by the impairment of MEK1/2 pathways. Caspase-1 independent death was observed in cells of different genetic backgrounds and interestingly occurred only in immature DCs. Maturation, triggered by different types of stimuli, led to full protection of DCs. These studies illustrate that the cellular damage inflicted by LT depends not only on the innate responses but also on the maturation stage of the cell, which modulates the more general caspase-1 independent responses.
PMCID: PMC2861895  PMID: 18194483
6.  Inflammasome recognition of influenza virus is essential for adaptive immune responses 
Influenza virus infection is recognized by the innate immune system through Toll like receptor (TLR) 7 and retinoic acid inducible gene I. These two recognition pathways lead to the activation of type I interferons and resistance to infection. In addition, TLR signals are required for the CD4 T cell and IgG2a, but not cytotoxic T lymphocyte, responses to influenza virus infection. In contrast, the role of NOD-like receptors (NLRs) in viral recognition and induction of adaptive immunity to influenza virus is unknown. We demonstrate that respiratory infection with influenza virus results in the activation of NLR inflammasomes in the lung. Although NLRP3 was required for inflammasome activation in certain cell types, CD4 and CD8 T cell responses, as well as mucosal IgA secretion and systemic IgG responses, required ASC and caspase-1 but not NLRP3. Consequently, ASC, caspase-1, and IL-1R, but not NLRP3, were required for protective immunity against flu challenge. Furthermore, we show that caspase-1 inflammasome activation in the hematopoietic, but not stromal, compartment was required to induce protective antiviral immunity. These results demonstrate that in addition to the TLR pathways, ASC inflammasomes play a central role in adaptive immunity to influenza virus.
PMCID: PMC2626661  PMID: 19139171
7.  The NLR gene family: An official nomenclature 
Immunity  2008;28(3):285-287.
Iimmune regulatory proteins such as CIITA, NAIP, IPAF, NOD1, NOD2, NALP1, cryopyrin/NALP3 are members of a family characterized by the presence of a nucleotide-binding domain (NBD) and leucine-rich repeats (LRR). Members of this gene family encode a protein structure similar to the NB-LRR subgroup of disease-resistance genes in plants and are involved in the sensing of pathogenic products and the regulation of cell signaling and apoptosis. Several members of this family have been associated with immunologic disorders. NOD2 for instance is associated with both Crohn's disease and Blau syndrome.
A variety of different names are currently used to describe this gene family, its subfamilies and individual genes, including CATERPILLER (CLR), NOD-LRR, NACHT-LRR, CARD, NALP, NOD, PAN and PYPAF, and this lack of consistency has led to a pressing need to unify the nomenclature. Consequently, we collectively propose the family designation NLR (nucleotide-binding domain and leucine-rich repeat containing) and provide unique and standardized gene designations for all family members.
PMCID: PMC2630772  PMID: 18341998
8.  Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome 
The Journal of Experimental Medicine  2007;204(13):3235-3245.
Pseudomonas aeruginosa is a Gram-negative bacterium that causes opportunistic infections in immunocompromised individuals. P. aeruginosa employs a type III secretion system to inject effector molecules into the cytoplasm of the host cell. This interaction with the host cell leads to inflammatory responses that eventually result in cell death. We show that infection of macrophages with P. aeruginosa results in activation of caspase-1 in an IPAF-dependent, but flagellin-independent, manner. Macrophages deficient in IPAF or caspase-1 were markedly resistant to P. aeruginosa–induced cell death and release of the proinflammatory cytokine interleukin (IL)-1β. A subset of P. aeruginosa isolates express the effector molecule exoenzyme U (ExoU), which we demonstrate is capable of inhibiting caspase-1–driven proinflammatory cytokine production. This study shows a key role for IPAF and capase-1 in innate immune responses to the pathogen P. aeruginosa, and also demonstrates that virulent ExoU-expressing strains of P. aeruginosa can circumvent this innate immune response.
PMCID: PMC2150987  PMID: 18070936
9.  Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis 
The Journal of Experimental Medicine  2006;203(6):1407-1412.
Caspase-1 is activated by a variety of stimuli after the assembly of the “inflammasome,” an activating platform made up of a complex of the NOD-LRR family of proteins. Caspase-1 is required for the secretion of proinflammatory cytokines, such as interleukin (IL)-1β and IL-18, and is involved in the control of many bacterial infections. Paradoxically, however, its absence has been reported to confer resistance to oral infection by Salmonella typhimurium. We show here that absence of caspase-1 or components of the inflammasome does not result in resistance to oral infection by S. typhimurium, but rather, leads to increased susceptibility to infection.
PMCID: PMC2118315  PMID: 16717117

Results 1-9 (9)