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In this review poster, we researched the function, regulation, and structure of NF-κB as it relates to carcinogenesis. Found in almost all animal cells, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a transcription factor that plays various roles in cellular proliferation, cell survival, inflammation, and T cell activation. There are two different NF-κB signaling pathways: the canonical pathway and the non-canonical pathway. NF-κB forms a p50/Rel A heterodimer in the canonical pathway and a p52/ Rel B heterodimer in the non-canonical pathway. NF-κB protein is normally sequestered in the cytoplasm as an inactive complex with a κB inhibitor (IκB) protein. Outside stimuli such as reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-α) activate cell surface receptors such as Toll-Like Receptors (TLRs) and Receptor Activators of NF-κB (RANK). These surface receptors, in turn, activate IκB kinase (IKK). IKK phosphorylates IκB, which causes ubiquitination of IκB, signaling proteasomes to degrade it. NF-κB then enters the nucleus through a nuclear pore and forms a transcription complex with coactivators and RNA polymerase. NF-κB binds to specific DNA-binding sites to induce transcription. One of the target genes of NF-κB encodes IκBs, so NF-κB regulates its own activity through a negative feedback loop. Because the cell maintains storage of the signaling protein NF-κB in the cytoplasm, NF-κB allows the cell to respond to sudden stimuli by activating quick changes in gene expression. Because proteins that promote cellular proliferation and cell survival are mainly transcribed through NF-κB activation, uncontrolled overactivation of this transcription factor has major implications in carcinogenesis. Many types of cancer cells have high levels of constitutively active NF-κB. Mutations in the genes for NF-κB itself or its inhibitors such as IκBs often found in cancer cells can cause cells to accelerate their proliferation or confer resistance to apoptosis. Some types of cancer cells secrete signaling molecules, inducing improper NF-κB activity. Because of the tumor promoting characteristics of NF-κB activation, a focus of current research is to find methods of suppressing NF-κB to kill cancer cells or slow their growth. We designed a 3D-printed model of the p50/RelA NF-κB protein using Jmol to highlight the relationship between its structure and function. Citation Format: Donian I. Chyong, Aurian Naderi, Chase Lee, Ty Arpornsuksant, Allison Lu, Megha Dilip, Margaret Zhang, Young-Joon Surh, Eun-Ji Lee, Hye-Kyung Na. Connections between NF-κB misregulation and carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3533. doi:10.1158/1538-7445.AM2017-3533

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The CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) protein is a member of the ABC (ATP‐binding cassette) family, which functions as a low conductance channel regulating the flow of certain anions (especially chloride and thiocyanate) across membranes of epithelial cells, allowing for osmosis‐based regulation of mucus consistency. The proper function of CFTR depends on the amino acid phenylalanine at position 508, which mediates a tertiary interaction between the surface of the N‐terminal nucleotide‐binding domain and cytoplasmic loop‐4 in the C‐terminal membrane‐spanning domain. Miscoding caused by the most common identified mutation, ΔF508, results in loss of phenylalanine by deletion of base pairs G, A, and A from the sequence “T‐A‐G” at position 507 and adjacent “A‐A‐A”, resulting in a codon made for isoleucine, but not for phenylalanine. Inheritance of two copies of the mutation causes part of the CFTR protein to misfold and degrade, not becoming fully processed in the endoplasmic reticulum. This mutation, among others, leads to a class II mutation of cystic fibrosis. The misfolded CFTR is either not transported to the surface of the membrane or is only transported in residual amounts, preventing the regulation of mucus consistency and causes cystic fibrosis. The mechanism of the ATP‐dependent gating mutation in CFTR protein can be further understood through modeling. Understanding the mutation that causes the misfolding of CFTR can help develop new treatments for those afflicted with cystic fibrosis. Walton High School SMART (Students Modeling A Research Topic) Team has designed a model of CFTR using 3D printing technology to investigate structure‐function relationships.

15‐Hydroxyprostaglandin dehydrogenase (15‐PGDH) is the key enzyme that catalyzes the degradation of prostaglandin E2 (PGE2). The expression of 15‐PGDH is ubiquitously down‐regulated in various cancers. Whereas, overexpression of 15‐PGDH in cancer cells causes apoptosis, cell cycle arrest, and inhibition of metastasis, and hence considered as a tumor suppressor. Hypermethylation of CpG islands in the gene promoter region is an important mechanism to silence the expression of 15‐PGDH and contributes to cancer formation. 15‐PGDH physiologically antagonizes cyclooxygenase‐2 (COX‐2), an enzyme involved in inflammation and carcinogenesis. Therefore, downregulation of 15‐PGDH and overexpression of COX‐2 may coordinately increase the levels of PGE2 and exacerbate the carcinogenic process. 15‐Deoxy‐Δ 12,14 ‐prostaglandin J2, a product of the COX‐2 enzymatic pathway, upregulates the expression of 15‐PGDH in breast cancer MDA‐MD‐231 cells in a negative feedback loop. 15‐PGDH is directly regulated by the TGF‐tumor suppressor pathway. In addition to cancer research, current research involves investigating 15‐PGDH as a potential avenue for tissue regeneration. Inhibition of 15‐PGDH has been found to potentiate hematopoietic recovery in mice receiving a bone marrow. 15‐PGDH has also been found to play a central role in determination of active prostaglandin concentrations during pregnancy and may be competitively regulated by progesterone and cortisol. Mutations in the gene coding for 15‐PGDH can also cause digital clubbing, the swelling of the distal parts of the finger. Research on 15‐PGDH will unlock treatment methods for patients suffering from a wide variety of illnesses. We printed a 3D model of the 15‐PGDH protein structure to investigate the relationship between structure and function.Support or Funding InformationWalton High School SMART (Students Modeling a Research Topic) Team is sponsored by Milwaukee School of Engineering.