Importantly, STAT3 activation occurs in both cancer cells and the many immune cells that infiltrate tumors, among which myeloid-derived suppressor cells (MDSCs). Moreover, a number of genes induced by STAT3 provide a positive feedback and as such keep the STAT3 pathway continuously activated. This is explained by the fact that many of the triggers that activate STAT3 are abundantly present in the tumor microenvironment (TME). A large body of evidence has shown that STAT3 is constitutively activated in many mouse tumor models, and more importantly in human cancers including breast, liver, lung, pancreas, prostate, skin, hematological and brain cancers. In addition, STAT3 levels can be regulated through ubiquitination-dependent proteosomal degradation. These families of STAT3 regulating proteins interfere with STAT3 binding to DNA, hamper tyrosine kinases and remove phosphates from activated STAT3, respectively. Īll transcriptional activity requires tight control, which in the case of STAT3 is performed by various negative regulators such as protein inhibitor of activated STAT proteins, suppressors of cytokine signaling (SOCS) proteins and protein tyrosine phosphatases. Also acetylation of lysine 685 has been described as a mode of STAT3 activation and a way to enhance the stability of STAT3 dimers. Phosphorylation of STAT3 results in its dimerization, which enables STAT3 to act as a transcriptional activator of various target genes. Phosphorylation on tyrosine 705 can be regulated by different tyrosine kinases and by members of the Janus-activated kinases (JAK), whereas phosphorylation of serine 727 can be regulated by protein kinase C, mitogen-activated protein kinases and cyclin-dependent kinase 5. Depending on the trigger, STAT3 activation occurs through phosphorylation on tyrosine 705 or serine 727. Activation of STAT3 can be triggered through a multitude of factors among which interleukin-6 (IL-6) like cytokines, colony stimulating factors (CSF) and leptin, interferon (IFN) as well as IL-2 family members, and growth factors like epidermal growth factor. Similar to its other family members, STAT3 is present in non-stimulated cells in an inactive cytoplasmic form. Because STAT3 is evolutionary the most conserved, it's considered to be a very important member of the STAT family. The signal transducer and activator of transcription (STAT) family is comprised of 7 members that are encoded by distinct genes. INTRODUCTION TO SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |