Stat3 as an Oncogene
Source: Cell, Vol. 98 (3): 295-303, 1999
Date: 2000/3/22
Abstract:
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.
Reference:
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.
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3. Darnell, J.E., Jr. (1997). STATs and gene regulation. Science
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