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W2169727912 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. 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. human epidermal growth factorreceptor heregulin-β1 epidermal growth factor EGF receptor anti-EGF receptor antibody monoclonal antibody anti-HER2 recombinant-derived humanized mAb. hnRNP K, heterogeneous nuclear ribonucleoprotein K gene discovery array K homology polyacrylamide gel electrophoresis transforming growth factor Growth factors and their receptors play an important role in regulating proliferation of epithelial cells. Abnormalities in the expression, structure, or activity of their proto-oncogene products contribute to the development and pathogenesis of cancer. For example, the human epidermal growth factorreceptor, HER1,1is overexpressed in a large number of epithelial tumor cells (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4581) Google Scholar). HER2, the second member of the HER family, shares extensive sequence homology with the tyrosine kinase domain of HER1 (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4581) Google Scholar, 2Hynes N.C. Stern D.F. Biochim. Biophys. Acta. 1994; 1198: 165-184Crossref PubMed Scopus (998) Google Scholar, 3Alroy I. Yarden Y. FEBS Lett. 1997; 410: 83-86Crossref PubMed Scopus (650) Google Scholar) and is overexpressed, amplified, or both in a number of human malignancies, including breast. Recently, HER3 and HER4 have been added to this receptor family (2Hynes N.C. Stern D.F. Biochim. Biophys. Acta. 1994; 1198: 165-184Crossref PubMed Scopus (998) Google Scholar, 3Alroy I. Yarden Y. FEBS Lett. 1997; 410: 83-86Crossref PubMed Scopus (650) Google Scholar). Regulation of these receptor family members is complex, and they can be trans-activated in a ligand-dependent manner. For example, binding of heregulin-β1 (HRG) to HER3 or HER4 can activate the HER2 as a result of HER2/HER3 or HER4/HER2 heterodimeric interactions (2Hynes N.C. Stern D.F. Biochim. Biophys. Acta. 1994; 1198: 165-184Crossref PubMed Scopus (998) Google Scholar, 3Alroy I. Yarden Y. FEBS Lett. 1997; 410: 83-86Crossref PubMed Scopus (650) Google Scholar, 4Zhang K. Sun J. Liu N. Wen D. Chang D. Thomas A. Yoshinaga S.K. J. Biol. Chem. 1996; 271: 3884-3890Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar). HER1 and HER2 have been shown to induce transformation in recipient cells (2Hynes N.C. Stern D.F. Biochim. Biophys. Acta. 1994; 1198: 165-184Crossref PubMed Scopus (998) Google Scholar, 3Alroy I. Yarden Y. FEBS Lett. 1997; 410: 83-86Crossref PubMed Scopus (650) Google Scholar, 4Zhang K. Sun J. Liu N. Wen D. Chang D. Thomas A. Yoshinaga S.K. J. Biol. Chem. 1996; 271: 3884-3890Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar), possibly because of excessive activation of signal transduction pathways. In contrast, transformation by HER3 or HER4 requires the presence of HER1 or HER2 (5Carraway K.L. Cantley L.C. Cell. 1994; 78: 5-8Abstract Full Text PDF PubMed Scopus (583) Google Scholar).Since growth factors regulate the proliferation of cancer cells by activating cell-surface receptors, one approach to controlling cell proliferation is to use antireceptor-blocking monoclonal antibodies to interfere with growth factor receptor-mediated autocrine or paracrine growth stimulation (6Kawamoto T. Sato J.D. Le A. Polikoff J. Sato G. Mendelsohn J. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 1337-1341Crossref PubMed Scopus (687) Google Scholar). C225, the human murine chimeric antibody against the EGF receptor (EGFR), blocks binding of ligand and prevents ligand-induced activation of receptor tyrosine kinase (6Kawamoto T. Sato J.D. Le A. Polikoff J. Sato G. Mendelsohn J. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 1337-1341Crossref PubMed Scopus (687) Google Scholar, 7Gill G.N. Kawamoto T. Cochet C. Le A. Sato J.D. Masui H. MacLeod C.L. Mendelsohn J. J. Biol. Chem. 1984; 259: 755-7760Google Scholar). C225 therapy has been success in phase I and phase IIA multicenter clinical trials in combination with chemotherapy or radiation (8Mendelsohn J. Clin. Cancer Res. 2000; 3: 2703-2707Google Scholar, 9Baselga J. Pfister D. Cooper M.R. Cohen R. Burtness B. Bos M. D'Andrea G. Seidman A. Norton L. Gunnett K. Anderson V. Waksal H. Mendelsohn J. J. Clin. Oncol. 2000; 18: 904-914Crossref PubMed Google Scholar, 10Perez-Soler R. Shin D.M. Donato N. Radinsky R. Khuri F. Glisson B.S. Shin H. Matsumoto T. Lawhorn K. Waksal H. Hong W.K. Mendelsohn J. Proc. Annu. Meet. Am. Soc. Clin. Oncol. 1998; 17 (Abstr. 1514): 393aGoogle Scholar, 11Mendelsohn J. Shin D.M. Donato N. Khuri F. Radinsky R. Glisson B.S. Shin H.J. Metz E. Pfister D. Perez-Soler R. Lawhorn K. Matsumoto T. Gunnett K. Falcey J. Waksal H. Hong W.K. Proc. Annu. Meet. Am. Soc. Clin. Oncol. 1999; 18 (Abstr. 1502): 389aGoogle Scholar). Similarly, the humanized form of anti-HER2 recombinant monoclonal antibody (HCT) inhibits the growth of breast cancer cells overexpressing HER2 (12Hudziak R.M. Lewis G.D. Winget M. Fendly B.M. Shepard H.M. Ullrich A. Mol. Cell. Biol. 1989; 9: 1165-1172Crossref PubMed Scopus (655) Google Scholar) and is currently being used as an effective drug against breast cancer both alone (13Cobleigh M.A. Vogel C.L. Tripathy D. Robert N.J. Scholl S. Fehrenbacher L. Wolter J.M. Paton V. Shak S. Lieberman G. Slamon D.J. J. Clin. Oncol. 1999; 17: 2639-2648Crossref PubMed Google Scholar) and in combination with chemotherapy (14Norton L. Slamon D. Leyland-Jones B. Wolter J. Fleming T. Eirmann W. Baselga J. Mendelsohn J. Bajamonde A. Ash M. Shak S. Proc. Annu. Meet. Am. Soc. Clin. Oncol. 1999; 18 (Abstr. 483): 127aGoogle Scholar). Antireceptor antibodies inhibit many processes, including mitogenesis, cell-cycle progression, invasion and metastasis, angiogenesis, and DNA repair (8Mendelsohn J. Clin. Cancer Res. 2000; 3: 2703-2707Google Scholar).In eukaryotic cells, heterogeneous nuclear RNAs (hnRNAs), from which mRNAs are generated by RNA processing, associate with specific nuclear proteins to form large hnRNP complexes (15Krecic A.M. Swanson M.S. Curr. Opin. Cell Biol. 1999; 11: 363-371Crossref PubMed Scopus (708) Google Scholar, 16Dreyfuss G. Matunis G.M. Pinol-Roma S. Burd C.G. Annu. Rev. Biochem. 1993; 62: 289-321Crossref PubMed Scopus (1326) Google Scholar). These hnRNP proteins bind pre-mRNAs and are believed to play important roles in mRNA biogenesis (17Swanson M.S. Lamond A.L. Pre-mRNA Processing. Springer-Verlag, Berlin1995: 17-33Crossref Google Scholar, 18Nigg E.A. Nature. 1997; 386: 779-787Crossref PubMed Scopus (911) Google Scholar), nucleocytoplasmic transport of mRNA (19Nakielny S. Dreyfuss G. Curr. Opin. Cell Biol. 1997; 9: 420-429Crossref PubMed Scopus (192) Google Scholar, 20Pinol-Roma S. Dreyfuss G. Science. 1991; 253: 312-314Crossref PubMed Scopus (173) Google Scholar, 21Pinol-Roma S. Dreyfuss G. Nature. 1992; 355: 730-732Crossref PubMed Scopus (737) Google Scholar), and cytoplasmic mRNA trafficking (22Carson J.H. Kwon S. Barbarese E. Curr. Opin. Neurobiol. 1998; 8: 607-612Crossref PubMed Scopus (116) Google Scholar). To date, about 20 hnRNPs (A through U) have been identified. HnRNP K, the major poly(iC)-binding protein, has several structural features not shared with other hnRNP proteins (23Matunis M.J. Michael W.M. Dreyfuss G. Mol. Cell. Biol. 1992; 12: 164-171Crossref PubMed Scopus (235) Google Scholar). For example, the binding of hnRNP K to nucleic acid is mediated by three repeat motifs termed the KH (K homology) domains rather than by the consensus RNA-binding sequence found in other hnRNP proteins (23Matunis M.J. Michael W.M. Dreyfuss G. Mol. Cell. Biol. 1992; 12: 164-171Crossref PubMed Scopus (235) Google Scholar, 24Siomi H. Matunis M.J. Michael W.M. Dreyfuss G. Nucleic Acids Res. 1993; 21: 1193-1198Crossref PubMed Scopus (453) Google Scholar). The KH domain is an evolutionarily conserved RNA-binding motif also found in fragile X protein FMR1 (25Siomi H. Choi M. Siomi M.C. Nussbaum R.L. Dreyfuss G. Cell. 1994; 77: 33-39Abstract Full Text PDF PubMed Scopus (380) Google Scholar), meiosis-specific splicing factor MER1 (26Engebbrecht J. Roeder G.S. Mol. Cell. Biol. 1990; 10: 2379-2389Crossref PubMed Scopus (103) Google Scholar), and paraneoplastic Ri autoantigen (27Buckanovich R.J. Posner J.B. Darnell R.B. Neuron. 1993; 11: 657-672Abstract Full Text PDF PubMed Scopus (265) Google Scholar). In addition, hnRNP K binds single-stranded DNA in vitro (28Tomonaga T. Levens D. J. Biol. Chem. 1995; 270: 4875-4881Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar) and has been identified as a sequence-specific DNA-binding protein (29Gaillard C. Cabannes E. Strauss F. Nucleic Acids Res. 1994; 22: 4183-4186Crossref PubMed Scopus (29) Google Scholar), consistent with its proposed role in transcription. More recently, hnRNP K has been shown to bind to a cis-element in the human c-myc promoter (30Takimoto M. Tomonaga T. Matunis M. Avigan M. Krutzsch H. Dreyfuss G. Levens D. J. Biol. Chem. 1993; 268: 18249-18258Abstract Full Text PDF PubMed Google Scholar) and to activate c-myc expression (31Michelotti E.F. Michelotti G.A. Aronsohn A.I. Levens D. Mol. Cell. Biol. 1996; 16: 2350-2360Crossref PubMed Scopus (312) Google Scholar) by promoting the synthesis of c-myc mRNA from a reporter gene (32Lee M.-H. Mori S. Raychaudhuri P. J. Biol. Chem. 1996; 271: 3420-3427Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). The hnRNP K protein can also interact with some proto-oncogene products and to act as a docking platform in signal transduction cascades (33Bustelo X.R. Suen K.L. Michael W.M. Dreyfuss G. Barbacid M. Mol. Cell. Biol. 1995; 15: 1324-1332Crossref PubMed Scopus (90) Google Scholar, 34Van Seuningen I. Ostrowski J. Bustelo X.R. Sleath P.R. Bomsztyk K. J. Biol. Chem. 1995; 270: 26976-26985Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar). The potential involvement of hnRNP in transformation was suspected, four splice variants of hnRNP K are up-regulated in SV40-transformed cells (35Dejgaard K. Leffers H. Rasmussen H.H. Madsen P. Kruse T.A. Gesser B. Nielsen H. Celis J.E. J. Mol. Biol. 1994; 236: 33-48Crossref PubMed Scopus (78) Google Scholar), and hnRNP B1 is the only other member of the hnRNP family, beside hnRNP K that is overexpressed in human lung cancers (36Sueoka E. Goto Y. Sueoka N. Kai Y. Kozu T. Fujiki H. Cancer Res. 1999; 59: 1404-1407PubMed Google Scholar). Despite the widely believed involvement of hnRNP K in post-transcriptional control, its possible regulation by the EGF family and by therapeutic antireceptor antibodies remains unexplored.To identify genes whose expression may be modulated by the activity of the EGF family of receptors because of ligand-induced activation of receptor tyrosine kinases or inhibition of receptor-associated tyrosine kinase activation, we used a human cDNA array approach to isolate cDNAs differentially expressed in the presence and absence of antireceptor antibodies. We identified one clone that was identical to human hnRNP K. In human breast cancer cells, EGF and HRG induced hnRNP K mRNA and protein expression that could be effectively blocked by pretreatment with antireceptor monoclonal antibodies. Our results also suggested that hnRNP K is involved in EGF- or HRG-induced transcription from the c-myc promoter and that hnRNP K expression can be used as a molecular monitor to assess the anti-tumor action of therapeutic antireceptor agents. Growth factors and their receptors play an important role in regulating proliferation of epithelial cells. Abnormalities in the expression, structure, or activity of their proto-oncogene products contribute to the development and pathogenesis of cancer. For example, the human epidermal growth factorreceptor, HER1,1is overexpressed in a large number of epithelial tumor cells (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4581) Google Scholar). HER2, the second member of the HER family, shares extensive sequence homology with the tyrosine kinase domain of HER1 (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4581) Google Scholar, 2Hynes N.C. Stern D.F. Biochim. Biophys. Acta. 1994; 1198: 165-184Crossref PubMed Scopus (998) Google Scholar, 3Alroy I. Yarden Y. FEBS Lett. 1997; 410: 83-86Crossref PubMed Scopus (650) Google Scholar) and is overexpressed, amplified, or both in a number of human malignancies, including breast. Recently, HER3 and HER4 have been added to this receptor family (2Hynes N.C. Stern D.F. Biochim. Biophys. Acta. 1994; 1198: 165-184Crossref PubMed Scopus (998) Google Scholar, 3Alroy I. Yarden Y. FEBS Lett. 1997; 410: 83-86Crossref PubMed Scopus (650) Google Scholar). Regulation of these receptor family members is complex, and they can be trans-activated in a ligand-dependent manner. For example, binding of heregulin-β1 (HRG) to HER3 or HER4 can activate the HER2 as a result of HER2/HER3 or HER4/HER2 heterodimeric interactions (2Hynes N.C. Stern D.F. Biochim. Biophys. Acta. 1994; 1198: 165-184Crossref PubMed Scopus (998) Google Scholar, 3Alroy I. Yarden Y. FEBS Lett. 1997; 410: 83-86Crossref PubMed Scopus (650) Google Scholar, 4Zhang K. Sun J. Liu N. Wen D. Chang D. Thomas A. Yoshinaga S.K. J. Biol. Chem. 1996; 271: 3884-3890Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar). HER1 and HER2 have been shown to induce transformation in recipient cells (2Hynes N.C. Stern D.F. Biochim. Biophys. Acta. 1994; 1198: 165-184Crossref PubMed Scopus (998) Google Scholar, 3Alroy I. Yarden Y. FEBS Lett. 1997; 410: 83-86Crossref PubMed Scopus (650) Google Scholar, 4Zhang K. Sun J. Liu N. Wen D. Chang D. Thomas A. Yoshinaga S.K. J. Biol. Chem. 1996; 271: 3884-3890Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar), possibly because of excessive activation of signal transduction pathways. In contrast, transformation by HER3 or HER4 requires the presence of HER1 or HER2 (5Carraway K.L. Cantley L.C. Cell. 1994; 78: 5-8Abstract Full Text PDF PubMed Scopus (583) Google Scholar). Since growth factors regulate the proliferation of cancer cells by activating cell-surface receptors, one approach to controlling cell proliferation is to use antireceptor-blocking monoclonal antibodies to interfere with growth factor receptor-mediated autocrine or paracrine growth stimulation (6Kawamoto T. Sato J.D. Le A. Polikoff J. Sato G. Mendelsohn J. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 1337-1341Crossref PubMed Scopus (687) Google Scholar). C225, the human murine chimeric antibody against the EGF receptor (EGFR), blocks binding of ligand and prevents ligand-induced activation of receptor tyrosine kinase (6Kawamoto T. Sato J.D. Le A. Polikoff J. Sato G. Mendelsohn J. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 1337-1341Crossref PubMed Scopus (687) Google Scholar, 7Gill G.N. Kawamoto T. Cochet C. Le A. Sato J.D. Masui H. MacLeod C.L. Mendelsohn J. J. Biol. Chem. 1984; 259: 755-7760Google Scholar). C225 therapy has been success in phase I and phase IIA multicenter clinical trials in combination with chemotherapy or radiation (8Mendelsohn J. Clin. Cancer Res. 2000; 3: 2703-2707Google Scholar, 9Baselga J. Pfister D. Cooper M.R. Cohen R. Burtness B. Bos M. D'Andrea G. Seidman A. Norton L. Gunnett K. Anderson V. Waksal H. Mendelsohn J. J. Clin. Oncol. 2000; 18: 904-914Crossref PubMed Google Scholar, 10Perez-Soler R. Shin D.M. Donato N. Radinsky R. Khuri F. Glisson B.S. Shin H. Matsumoto T. Lawhorn K. Waksal H. Hong W.K. Mendelsohn J. Proc. Annu. Meet. Am. Soc. Clin. Oncol. 1998; 17 (Abstr. 1514): 393aGoogle Scholar, 11Mendelsohn J. Shin D.M. Donato N. Khuri F. Radinsky R. Glisson B.S. Shin H.J. Metz E. Pfister D. Perez-Soler R. Lawhorn K. Matsumoto T. Gunnett K. Falcey J. Waksal H. Hong W.K. Proc. Annu. Meet. Am. Soc. Clin. Oncol. 1999; 18 (Abstr. 1502): 389aGoogle Scholar). Similarly, the humanized form of anti-HER2 recombinant monoclonal antibody (HCT) inhibits the growth of breast cancer cells overexpressing HER2 (12Hudziak R.M. Lewis G.D. Winget M. Fendly B.M. Shepard H.M. Ullrich A. Mol. Cell. Biol. 1989; 9: 1165-1172Crossref PubMed Scopus (655) Google Scholar) and is currently being used as an effective drug against breast cancer both alone (13Cobleigh M.A. Vogel C.L. Tripathy D. Robert N.J. Scholl S. Fehrenbacher L. Wolter J.M. Paton V. Shak S. Lieberman G. Slamon D.J. J. Clin. Oncol. 1999; 17: 2639-2648Crossref PubMed Google Scholar) and in combination with chemotherapy (14Norton L. Slamon D. Leyland-Jones B. Wolter J. Fleming T. Eirmann W. Baselga J. Mendelsohn J. Bajamonde A. Ash M. Shak S. Proc. Annu. Meet. Am. Soc. Clin. Oncol. 1999; 18 (Abstr. 483): 127aGoogle Scholar). Antireceptor antibodies inhibit many processes, including mitogenesis, cell-cycle progression, invasion and metastasis, angiogenesis, and DNA repair (8Mendelsohn J. Clin. Cancer Res. 2000; 3: 2703-2707Google Scholar). In eukaryotic cells, heterogeneous nuclear RNAs (hnRNAs), from which mRNAs are generated by RNA processing, associate with specific nuclear proteins to form large hnRNP complexes (15Krecic A.M. Swanson M.S. Curr. Opin. Cell Biol. 1999; 11: 363-371Crossref PubMed Scopus (708) Google Scholar, 16Dreyfuss G. Matunis G.M. Pinol-Roma S. Burd C.G. Annu. Rev. Biochem. 1993; 62: 289-321Crossref PubMed Scopus (1326) Google Scholar). These hnRNP proteins bind pre-mRNAs and are believed to play important roles in mRNA biogenesis (17Swanson M.S. Lamond A.L. Pre-mRNA Processing. Springer-Verlag, Berlin1995: 17-33Crossref Google Scholar, 18Nigg E.A. Nature. 1997; 386: 779-787Crossref PubMed Scopus (911) Google Scholar), nucleocytoplasmic transport of mRNA (19Nakielny S. Dreyfuss G. Curr. Opin. Cell Biol. 1997; 9: 420-429Crossref PubMed Scopus (192) Google Scholar, 20Pinol-Roma S. Dreyfuss G. Science. 1991; 253: 312-314Crossref PubMed Scopus (173) Google Scholar, 21Pinol-Roma S. Dreyfuss G. Nature. 1992; 355: 730-732Crossref PubMed Scopus (737) Google Scholar), and cytoplasmic mRNA trafficking (22Carson J.H. Kwon S. Barbarese E. Curr. Opin. Neurobiol. 1998; 8: 607-612Crossref PubMed Scopus (116) Google Scholar). To date, about 20 hnRNPs (A through U) have been identified. HnRNP K, the major poly(iC)-binding protein, has several structural features not shared with other hnRNP proteins (23Matunis M.J. Michael W.M. Dreyfuss G. Mol. Cell. Biol. 1992; 12: 164-171Crossref PubMed Scopus (235) Google Scholar). For example, the binding of hnRNP K to nucleic acid is mediated by three repeat motifs termed the KH (K homology) domains rather than by the consensus RNA-binding sequence found in other hnRNP proteins (23Matunis M.J. Michael W.M. Dreyfuss G. Mol. Cell. Biol. 1992; 12: 164-171Crossref PubMed Scopus (235) Google Scholar, 24Siomi H. Matunis M.J. Michael W.M. Dreyfuss G. Nucleic Acids Res. 1993; 21: 1193-1198Crossref PubMed Scopus (453) Google Scholar). The KH domain is an evolutionarily conserved RNA-binding motif also found in fragile X protein FMR1 (25Siomi H. Choi M. Siomi M.C. Nussbaum R.L. Dreyfuss G. Cell. 1994; 77: 33-39Abstract Full Text PDF PubMed Scopus (380) Google Scholar), meiosis-specific splicing factor MER1 (26Engebbrecht J. Roeder G.S. Mol. Cell. Biol. 1990; 10: 2379-2389Crossref PubMed Scopus (103) Google Scholar), and paraneoplastic Ri autoantigen (27Buckanovich R.J. Posner J.B. Darnell R.B. Neuron. 1993; 11: 657-672Abstract Full Text PDF PubMed Scopus (265) Google Scholar). In addition, hnRNP K binds single-stranded DNA in vitro (28Tomonaga T. Levens D. J. Biol. Chem. 1995; 270: 4875-4881Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar) and has been identified as a sequence-specific DNA-binding protein (29Gaillard C. Cabannes E. Strauss F. Nucleic Acids Res. 1994; 22: 4183-4186Crossref PubMed Scopus (29) Google Scholar), consistent with its proposed role in transcription. More recently, hnRNP K has been shown to bind to a cis-element in the human c-myc promoter (30Takimoto M. Tomonaga T. Matunis M. Avigan M. Krutzsch H. Dreyfuss G. Levens D. J. Biol. Chem. 1993; 268: 18249-18258Abstract Full Text PDF PubMed Google Scholar) and to activate c-myc expression (31Michelotti E.F. Michelotti G.A. Aronsohn A.I. Levens D. Mol. Cell. Biol. 1996; 16: 2350-2360Crossref PubMed Scopus (312) Google Scholar) by promoting the synthesis of c-myc mRNA from a reporter gene (32Lee M.-H. Mori S. Raychaudhuri P. J. Biol. Chem. 1996; 271: 3420-3427Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). The hnRNP K protein can also interact with some proto-oncogene products and to act as a docking platform in signal transduction cascades (33Bustelo X.R. Suen K.L. Michael W.M. Dreyfuss G. Barbacid M. Mol. Cell. Biol. 1995; 15: 1324-1332Crossref PubMed Scopus (90) Google Scholar, 34Van Seuningen I. Ostrowski J. Bustelo X.R. Sleath P.R. Bomsztyk K. J. Biol. Chem. 1995; 270: 26976-26985Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar). The potential involvement of hnRNP in transformation was suspected, four splice variants of hnRNP K are up-regulated in SV40-transformed cells (35Dejgaard K. Leffers H. Rasmussen H.H. Madsen P. Kruse T.A. Gesser B. Nielsen H. Celis J.E. J. Mol. Biol. 1994; 236: 33-48Crossref PubMed Scopus (78) Google Scholar), and hnRNP B1 is the only other member of the hnRNP family, beside hnRNP K that is overexpressed in human lung cancers (36Sueoka E. Goto Y. Sueoka N. Kai Y. Kozu T. Fujiki H. Cancer Res. 1999; 59: 1404-1407PubMed Google Scholar). Despite the widely believed involvement of hnRNP K in post-transcriptional control, its possible regulation by the EGF family and by therapeutic antireceptor antibodies remains unexplored. To identify genes whose expression may be modulated by the activity of the EGF family of receptors because of ligand-induced activation of receptor tyrosine kinases or inhibition of receptor-associated tyrosine kinase activation, we used a human cDNA array approach to isolate cDNAs differentially expressed in the presence and absence of antireceptor antibodies. We identified one clone that was identical to human hnRNP K. In human breast cancer cells, EGF and HRG induced hnRNP K mRNA and protein expression that could be effectively blocked by pretreatment with antireceptor monoclonal antibodies. Our results also suggested that hnRNP K is involved in EGF- or HRG-induced transcription from the c-myc promoter and that hnRNP K expression can be used as a molecular monitor to assess the anti-tumor action of therapeutic antireceptor agents. We thank Genentech Inc. for anti-HER2 antibody and Imclone Systems, Inc. for C225." @default.
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W2169727912 date "2001-03-01" @default.
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W2169727912 title "Growth Factors Regulate Heterogeneous Nuclear Ribonucleoprotein K Expression and Function" @default.
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