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J. Biol. Chem., Vol. 276, Issue 13, 9699-9704, March 30, 2001
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From Department of Molecular and Cellular Oncology, The University
of Texas M. D. Anderson Cancer Center-108, Houston, Texas 77030
Epidermal growth factor (EGF) family of growth
factors and their receptors regulate normal and cancerous epithelial
cell proliferation, a process that can be suppressed by
antireceptor blocking antibodies. To identify genes whose
expression may be modulated by antireceptor blocking antibodies, we
performed a differential display screen with cells grown in the
presence or absence of antireceptor blocking antibodies; isolates from
one cDNA clone were 100% identical to human heterogeneous nuclear
ribonucleoprotein K (hnRNP K), a protein with a conserved KH motif and
RGG boxes, has been implicated in such functions as sequence-specific
DNA binding, transcription, RNA binding, and nucleocytoplasmic
shuttling. Both EGF and heregulin-
Growth Factors Regulate Heterogeneous Nuclear
Ribonucleoprotein K Expression and Function*
,
1 induced expression of
hnRNP K mRNA and protein in human breast cancer cells. This growth
factor-mediated hnRNP K expression was effectively blocked by
pretreatment of cultures with humanized anti-EGF receptor (EGFR)
antibody C225, or anti-human epidermal growth
factor receptor-2 (HER2) antibody. Anti-EGFR
monoclonal antibody also caused regression of human tumor xenografts
and reduction in hnRNP K levels in athymic mice. Samples from grade III
human breast cancer contained more hnRNP K protein than samples from
grade II cancer. Finally, overexpression of hnRNP K in breast cancer
cells significantly increased target c-myc promoter
activity and c-Myc protein, hnRNP K protein levels, and enhanced breast cancer cell proliferation and growth in an anchorage-independent manner. These results suggested that the activity of human EGF receptor
family members regulates hnRNP K expression by extracellular growth
promoting signals and that therapeutic humanized antibodies against
EGFR and HER2 can effectively block this function.
*
This work was supported by the National Institutes of Health
Grants CA80066 and CA65746, by the Breast Research program of The
University of Texas M. D. Anderson Cancer Center, and by
Bristol-Myers-Squibb Research Funds (to R. K.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present address: Unidade de Oncologia-Hospital de Santa Maria,
Lisbon 1500, Portugal.
§
Member of the Board of Directors of Imclone Systems, Inc. and has
stock options.
¶
To whom correspondence should be addressed. E-mail:
rkumar@mdanderson.org.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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