Animal Models of Colitis-Associated Carcinogenesis

Figure 2

The JAK/STAT3 signaling pathway transmits information from cytokine/chemical signals outside the cell, through the cell membrane, and into the gene promoters on the DNA in the cell nucleus, which causes DNA transcription and activity in the cell. After JAK is activated by autophosphorylation, STAT3 protein then binds to the phosphorylated receptor. STAT3 is phosphorylated and translocated into the cell nucleus, where it binds to DNA and promotes transcription of genes responsive to STAT. TGF-β controls proliferation, cellular differentiation, and it acts as an antiproliferative factor in normal epithelial cells, and at early stages of oncogenesis. In the SMAD pathway, the TGF-β dimers bind to a type-2 receptor which recruits and phosphorylates a type-1 receptor. The type-1 receptor then recruits and phosphorylates a SMAD. This SMAD then binds to the common SMAD and forms a heterodimeric complex. This complex then enters the cell nucleus where it acts as a transcription factor for the various genes, including those to activate the MAP Kinase pathway, which triggers apoptosis. The TAK1-NLK-STAT3 pathway cascade participates in TGF-β-mediated mesoderm induction. Finally, MyD88 is a universal adaptor protein that is used by most of TLRs to activate the transcription factor NF-κB. These signals are closely associated with colitis-associated cancer formation. The abbreviations used in this figure are: Erk, extracellular signal-regulated kinases (=MAPK); HAD, histone deacetylase; IKK, IκB inhibitor; IRAK, IL-1 receptor associated kinase; JAK, Janus kinase; NLK, nemo-like kinase; MAPK, microtubule-associated protein kinase; MEK, mitogen activated protein kinase; mTOR, mammalian target of rapamycin; MyD88, myeloid differentiation primary response gene 88; PI3K, phosphoinositide 3-kinase; STAT, signal transducer and activator of transcription; TAK, TGF-β activated kinase; TBR, TGF-β receptor; TCF, T cell factor; TGF, transforming growth factor; TLR, Toll-like receptor.