Growth Factors Regulate Heterogeneous Nuclear Ribonucleoprotein K Expression and Function

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

Research output: Contribution to journalArticle

106 Citations (Scopus)

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

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Heterogeneous-Nuclear Ribonucleoprotein K
Intercellular Signaling Peptides and Proteins
Epidermal Growth Factor Receptor
Blocking Antibodies
Breast Neoplasms
Cells
Cell proliferation
Epidermal Growth Factor
Proteins
Cell Proliferation
Proto-Oncogene Proteins c-myc
Neuregulin-1
Antibodies, Monoclonal, Humanized
Growth Factor Receptors
Antibodies
Cell growth
Transcription
Growth
Heterografts
Gene expression

ASJC Scopus subject areas

  • Biochemistry

Cite this

Growth Factors Regulate Heterogeneous Nuclear Ribonucleoprotein K Expression and Function. / Mandal, Mahitosh; Vadlamudi, Ratna K; Nguyen, Diep; Wang, Rui An; Costa, Luis; Bagheri-Yarmand, Rozita; Mendelsohn, John; Kumar, Rakesh.

In: Journal of Biological Chemistry, Vol. 276, No. 13, 30.03.2001, p. 9699-9704.

Research output: Contribution to journalArticle

Mandal, M, Vadlamudi, RK, Nguyen, D, Wang, RA, Costa, L, Bagheri-Yarmand, R, Mendelsohn, J & Kumar, R 2001, 'Growth Factors Regulate Heterogeneous Nuclear Ribonucleoprotein K Expression and Function', Journal of Biological Chemistry, vol. 276, no. 13, pp. 9699-9704. https://doi.org/10.1074/jbc.M008514200
Mandal, Mahitosh ; Vadlamudi, Ratna K ; Nguyen, Diep ; Wang, Rui An ; Costa, Luis ; Bagheri-Yarmand, Rozita ; Mendelsohn, John ; Kumar, Rakesh. / Growth Factors Regulate Heterogeneous Nuclear Ribonucleoprotein K Expression and Function. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 13. pp. 9699-9704.
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