Growth Factors Regulate Heterogeneous Nuclear Ribonucleoprotein K Expression and Function

Mahitosh Mandal, Ratna Vadlamudi, Diep Nguyen, Rui An Wang, Luis Costa, Rozita Bagheri-Yarmand, John Mendelsohn, Rakesh Kumar

Research output: Contribution to journalArticle

107 Scopus citations

Abstract

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-β1 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.

Original languageEnglish (US)
Pages (from-to)9699-9704
Number of pages6
JournalJournal of Biological Chemistry
Volume276
Issue number13
DOIs
StatePublished - Mar 30 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Mandal, M., Vadlamudi, R., Nguyen, D., Wang, R. A., Costa, L., Bagheri-Yarmand, R., Mendelsohn, J., & Kumar, R. (2001). Growth Factors Regulate Heterogeneous Nuclear Ribonucleoprotein K Expression and Function. Journal of Biological Chemistry, 276(13), 9699-9704. https://doi.org/10.1074/jbc.M008514200