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J Biol Chem, Vol. 273, Issue 25, 15574-15581, June 19, 1998
Function
From the Departments of Molecular Biology and Radiation Oncology,
Henry Ford Health System, Detroit, Michigan 48202-3450
Human translocation liposarcoma
(TLS)-CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP)
is a fusion oncoprotein found specifically in a malignant tumor of
adipose tissue and results from a t(12;16) translocation that fuses the
amino-terminal part of TLS to the entire coding region of CHOP. Being
that CHOP is a member of the C/EBP transcription factor family,
proteins that comprise part of the adipocyte differentiation machinery, we examined whether TLS-CHOP blocked adipocyte differentiation by
directly interfering with C/EBP function. Using a single-step retroviral infection protocol, either wild-type or mutant TLS-CHOP were
co-expressed along with C/EBP
in naïve NIH3T3 cells, and their ability to inhibit C/EBP-driven adipogenesis was determined. TLS-CHOP was extremely effective at blocking adipocyte differentiation when expressed at a level comparable to that observed in human myxoid
liposarcoma. This effect of TLS-CHOP required a functional leucine
zipper domain and correlated with its ability to heterodimerize with
C/EBP and inhibit C/EBP DNA binding and transactivation activity
in situ. In contrast, the TLS-CHOP basic region was
dispensable, making it unlikely that the inhibitory effect of TLS-CHOP
is attributable to unscheduled gene expression resulting from
TLS-CHOP's putative transactivation activity. Another adipogenic
transcription factor, PPAR
2, was able to rescue TLS-CHOP-inhibited
cells, indicating that TLS-CHOP interferes primarily with
C/EBP-driven adipogenesis and not with other requisite events of the
adipocyte differentiation program. Together, the results demonstrate
that TLS-CHOP blocks adipocyte differentiation by directly preventing
C/EBP from binding to and transactivating its target genes.
Moreover, they provide strong support for the thesis that a blockade to
normal differentiation is an important aspect of the cancer
process.
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