Resume

• 2011

  Franklin and Marshall College

  Lancaster

  PA

  Assistant Professor

  Franklin and Marshall College

• 2003

  UNC at Chapel Hill

  UNC at Chapel Hill

  UNC at Chapel Hill

  Franklin & Marshall College

  Lancaster

  Pennsylvania Area

  Associate Professor

• 1996

  Ph.D.

  Immunology

• 1991

  B.A.

  Biology

• Genetics

  Molecular Cloning

  Western Blotting

  Protein Expression

  Translational Research

  Immunohistochemistry

  Microscopy

  Cell Biology

  Flow Cytometry

  ELISA

  Tissue Culture

  Neuroscience

  Confocal Microscopy

  Biochemistry

  PCR

  Cell

  Cell Culture

  Molecular Biology

  Fluorescence Microscopy

  In Vivo

  NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-κB signaling

  Author List: Allen IC

  Wilson JE

  Schneider M

  Lich JD

  Roberts RA

  Arthur JC

  Woodford RM

  Davis BK

  Uronis JM

  Herfarth HH

  Jobin C

  Rogers AB

  Ting JP.\n\nIn vitro data suggest that a subgroup of NLR proteins

  including NLRP12

  inhibits the transcription factor NF-κB

  although physiologic and disease-relevant evidence is largely missing. Dysregulated NF-κB activity is associated with colonic inflammation and cancer

  and we found Nlrp12(-/-) mice were highly susceptible to colitis and colitis-associated colon cancer. Polyps isolated from Nlrp12(-/-) mice showed elevated noncanonical NF-κB activation and increased expression of target genes that were associated with cancer

  including Cxcl13 and Cxcl12. NLRP12 negatively regulated ERK and AKT signaling pathways in affected tumor tissues. Both hematopoietic- and nonhematopoietic-derived NLRP12 contributed to inflammation

  but the latter dominantly contributed to tumorigenesis. The noncanonical NF-κB pathway was regulated upon degradation of TRAF3 and activation of NIK. NLRP12 interacted with both NIK and TRAF3

  and Nlrp12(-/-) cells have constitutively elevated NIK

  p100 processing to p52 and reduced TRAF3. Thus

  NLRP12 is a checkpoint of noncanonical NF-κB

  inflammation

  and tumorigenesis.

  NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-κB signaling

  Marcus Mühlbauer

  Liang Chen

  Alex Petrucelli

  Author List: Wilson JE

  Petrucelli AS

  Chen L

  Koblansky AA

  Truax AD

  Oyama Y

  Rogers AB

  Brickey WJ

  Wang Y

  Schneider M

  Mühlbauer M

  Chou WC

  Barker BR

  Jobin C

  Allbritton NL3

  Ramsden DA

  Davis BK

  Ting JP.\n\n\nThe inflammasome activates caspase-1 and the release of interleukin-1β (IL-1β) and IL-18

  and several inflammasomes protect against intestinal inflammation and colitis-associated colon cancer (CAC) in animal models. The absent in melanoma 2 (AIM2) inflammasome is activated by double-stranded DNA

  and AIM2 expression is reduced in several types of cancer

  but the mechanism by which AIM2 restricts tumor growth remains unclear. We found that Aim2-deficient mice had greater tumor load than Asc-deficient mice in the azoxymethane/dextran sodium sulfate (AOM/DSS) model of colorectal cancer. Tumor burden was also higher in Aim2-/-/ApcMin/+ than in APCMin/+ mice. The effects of AIM2 on CAC were independent of inflammasome activation and IL-1β and were primarily mediated by a non-bone marrow source of AIM2. In resting cells

  AIM2 physically interacted with and limited activation of DNA-dependent protein kinase (DNA-PK)

  a PI3K-related family member that promotes Akt phosphorylation

  whereas loss of AIM2 promoted DNA-PK-mediated Akt activation. AIM2 reduced Akt activation and tumor burden in colorectal cancer models

  while an Akt inhibitor reduced tumor load in Aim2-/- mice. These findings suggest that Akt inhibitors could be used to treat AIM2-deficient human cancers.

  Inflammasome-independent role of AIM2 in suppressing colon tumorigenesis via DNA-PK and Akt

  Franklin & Marshall College