Stat3 as an Oncogene
Source: Cell, Vol. 98 (3): 295-303, 1999
STAT (signal transducer and activators of transcription) proteins are latent transcription factors that become activated by phosphorylation on a single tyrosine (near residue 700), typically in response to extracellular ligands. Active Stat dimers accumulate in the nucleus, recognize specific DNA elements and activate transcription. In many human cancers and transformed cell lines, Stat3 is persistently activates, and in cell culture, active Stat3 is either required for transformation, enhances transformation, or blocks apoptosis.
Oncogenes were first defined as
viral or mutated cellular genes that could confer a transformed phenotype
to cultured cells. When oncogenes were characterized at the molecular level,
many were found to be constitutively activated.
During the past several years, reports have accumulated indicating that human tumor samples contain constitutively activated Stats. In this paper, authors have engineered a constitutively dimerizeable Stat3 by substituting cysteine residues for specific amino acids within the C-terminal loop in the SH2 domain of the Stat3 molecule. This molecule is capable of driving transcription and induces cell transformation, thus qualifying Stat3 as a protooncogene.
1. Chen, X., Vinkemeier, U., Zhao, Y., Jeruzalmi, D., Darnell, J.E.,
Jr., and Kuriyan, J. (1998). Crystal structure of a tyrosine phosphorylated
STAT-1 dimer bound to DNA. Cell 93, 827-839.
2. Besser, D., Bromberg, J.F., Darnell, J.E., Jr. and Hanafusa, H. (1999). A single
amino acid substitution in the v-Eyk intracellular domain results in activation of Stat3 and enhances cellular transformation. Mol. Cell. Biol. 19, 1401-1409.
3. Darnell, J.E., Jr. (1997). STATs and gene regulation. Science 277, 1630-1635.