Growth factors regulate heterogeneous nuclear ribonucleoprotein K expression and function.
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-beta1 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.
Mandal
M
M
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center-108, Houston 77030, USA.
Vadlamudi
R
R
Nguyen
D
D
Wang
R A
RA
Costa
L
L
Bagheri-Yarmand
R
R
Mendelsohn
J
J
Kumar
R
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000378:metabolism; D002455:Cell Division; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D020869:Gene Expression Profiling; D016259:Genes, myc / Q000235:genetics; D006133:Growth Substances / Q000378:metabolism*; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D006801:Humans; D015151:Immunoblotting; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020890:Neuregulin-1 / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012261:Ribonucleoproteins / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors; D014018:Tissue Distribution; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D004247:DNA; D018076:DNA, Complementary; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D006133:Growth Substances; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D008024:Ligands; D020890:Neuregulin-1; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D012261:Ribonucleoproteins; C087230:heregulin beta1