M. Ubeda et al., STRESS-INDUCED BINDING OF THE TRANSCRIPTION FACTOR CHOP TO A NOVEL DNA CONTROL ELEMENT, Molecular and cellular biology, 16(4), 1996, pp. 1479-1489
CHOP (GADD153) is a mammalian nuclear protein that dimerizes with memb
ers of the C/EBP family of transcription factors, Absent under normal
growth conditions, CHOP is induced by the stress encountered during nu
trient deprivation, the acute-phase response, and treatment of cells w
ith certain toxins, The basic region of CHOP deviates considerably in
sequence from that of other C/EBP proteins, and CHOP-C/EBP heterodimer
s are incapable of binding to a common class of C/EBP sites, With resp
ect to such sites, CHOP serves as an inhibitor of the activity of C/EB
P proteins, However, recent studies indicate that certain functions of
CHOP, such as the induction of growth arrest by overexpression of the
wild-type protein and on transformation by the TLS-CHOP fusion protei
n, require an intact basic region, suggesting that DNA binding by CHOP
may be implicated in these activities, In this study an in vitro PCR-
based site selection assay was used to identify sequences bound by CHO
P-C/EBP dimers, These sequences were found to contain a unique core el
ement PuPuPuTGCAAT(A/C)CCC, Competition in DNA-binding assays, DNase I
footprint analysis, and methylation interference demonstrate that the
binding is sequence specific, Deletions in the basic region of CHOP l
ead to a loss of DNA binding, suggesting that CHOP participates in thi
s process, Stress induction in NIH 3T3 cells leads to the appearance o
f CHOP-containing DNA-binding activity, CHOP is found to contain a tra
nscriptional activation domain which is inducible by cellular stress,
lending further support to the notion that the protein can function as
a positively acting transcription factor, We conclude that CHOP may s
erve a dual role both as an inhibitor of the ability of C/EBP proteins
to activate some target genes and as a direct activator of others.