Annexin A2 Is a Novel RNA-binding Protein

Annexin A2 (ANXA2) is a Ca2+-binding protein that is up-regulated in virally transformed cell lines and in human tumors. Here, we show that ANXA2 binds directly to both ribonucleotide homopolymers and human c-myc RNA. ANXA2 was shown to bind specifically to poly(G) with high affinity (Kd = 60 nm) and not to poly(A), poly(C), or poly(U). The binding of ANXA2 to poly(G) required Ca2+ (A50% = 10 μm). The presence of RNA in the immunoprecipitates of ANXA2 isolated from HeLa cells established that ANXA2 formed a ribonucleoprotein complex in vivo. Sucrose gradient analysis showed that ANXA2 associates with ribonucleoprotein complexes and not with polyribosomes. Reverse transcriptase-PCR identified c-myc mRNA as a component of the ribonucleoprotein complex formed by ANXA2 in vivo, and binding studies confirmed a direct interaction between ANXA2 and c-myc mRNA. Transfection of LNCaP cells with the ANXA2 gene resulted in the up-regulation of c-Myc protein. These findings identify ANXA2 as a Ca2+-dependent RNA-binding protein that interacts with the mRNA of the nuclear oncogene, c-myc. Annexin A2 (ANXA2) is a Ca2+-binding protein that is up-regulated in virally transformed cell lines and in human tumors. Here, we show that ANXA2 binds directly to both ribonucleotide homopolymers and human c-myc RNA. ANXA2 was shown to bind specifically to poly(G) with high affinity (Kd = 60 nm) and not to poly(A), poly(C), or poly(U). The binding of ANXA2 to poly(G) required Ca2+ (A50% = 10 μm). The presence of RNA in the immunoprecipitates of ANXA2 isolated from HeLa cells established that ANXA2 formed a ribonucleoprotein complex in vivo. Sucrose gradient analysis showed that ANXA2 associates with ribonucleoprotein complexes and not with polyribosomes. Reverse transcriptase-PCR identified c-myc mRNA as a component of the ribonucleoprotein complex formed by ANXA2 in vivo, and binding studies confirmed a direct interaction between ANXA2 and c-myc mRNA. Transfection of LNCaP cells with the ANXA2 gene resulted in the up-regulation of c-Myc protein. These findings identify ANXA2 as a Ca2+-dependent RNA-binding protein that interacts with the mRNA of the nuclear oncogene, c-myc. The annexins are a family of more than 160 unique annexin proteins that are present in more than 65 different species ranging from fungi and protists to plants and higher vertebrates (1Gerke V. Moss S.E. Physiol. Rev. 2002; 82: 331-371Crossref PubMed Scopus (1628) Google Scholar). ANXA2 1The abbreviations used are: ANXA2, annexin A2; ATD, aminoterminal domain; CCD, carboxyl core domain; RNP, ribonucleoprotein; mRNP, messenger ribonucleoprotein; RT, reverse transcriptase; pCp, cytidine 3′,5′-bis(phosphate); TBS, Tris-buffered saline.1The abbreviations used are: ANXA2, annexin A2; ATD, aminoterminal domain; CCD, carboxyl core domain; RNP, ribonucleoprotein; mRNP, messenger ribonucleoprotein; RT, reverse transcriptase; pCp, cytidine 3′,5′-bis(phosphate); TBS, Tris-buffered saline. consists of an amino-terminal domain (ATD), which comprises the first 30 amino acid residues of the protein and the carboxyl core domain (CCD) composed of the remaining residues. The CCD of ANXA2 contains sites for binding Ca2+, phospholipid, F-actin and heparin (2Filipenko N.R. Waisman D.M. Annexins: Biological Importance and Annexin-related Pathologies. Landes Bioscience, Georgetown, TX2003: 127-156Crossref Google Scholar, 3Waisman D.M. Mol. Cell Biochem. 1995; 149: 301-322Crossref PubMed Scopus (262) Google Scholar). The ATD contains regulatory phosphorylation sites for both protein kinase C (Ser-25) and Src (Tyr-23). In fact, the first substrate discovered for Src was identified as a 36-kDa protein (ANXA2) that was phosphorylated upon transformation of cells with the Rous sarcoma virus (4Radke K. Martin G.S. Proc. Natl. Acad. Sci. U. S. A. 1979; 76: 5212-5216Crossref PubMed Scopus (153) Google Scholar). Subsequently, it was demonstrated that only about 10% of total cellular ANXA2 was phosphorylated in cells transformed by RSV (4Radke K. Martin G.S. Proc. Natl. Acad. Sci. U. S. A. 1979; 76: 5212-5216Crossref PubMed Scopus (153) Google Scholar, 5Erikson E. Erikson R.L. Cell. 1980; 21: 829-836Abstract Full Text PDF PubMed Scopus (215) Google Scholar). ANXA2 exists as three major species: a monomer, a heterodimer, or a heterotetramer (AIIt) (3Waisman D.M. Mol. Cell Biochem. 1995; 149: 301-322Crossref PubMed Scopus (262) Google Scholar). The heterodimer is composed of a single subunit of ANXA2 bound to a subunit of 3-phosphoglycerate kinase (6Jindal H.K. Chaney W.G. Anderson C.W. Davis R.G. Vishwanatha J.K. J. Biol. Chem. 1991; 266: 5169-5176Abstract Full Text PDF PubMed Google Scholar). The heterotetramer, on the other hand, comprises two subunits of ANXA2 linked together by a dimer of S100A10 (also referred to as p11), a member of the S100 family of Ca2+-binding proteins (7Erikson E. Tomasiewicz H.G. Erikson R.L. Mol. Cell. Biol. 1984; 4: 77-85Crossref PubMed Scopus (61) Google Scholar, 8Gerke V. Weber K. EMBO J. 1984; 3: 227-233Crossref PubMed Scopus (389) Google Scholar, 9Glenney Jr., J.R. Tack B.F. Proc. Natl. Acad. Sci. U. S. A. 1985; 82: 7884-7888Crossref PubMed Scopus (211) Google Scholar, 10Gerke V. Weber K. EMBO J. 1985; 4: 2917-2920Crossref PubMed Scopus (191) Google Scholar). The relative amounts of heterotetrameric versus monomeric ANXA2 are variable depending on the cell or tissue examined and range from 100% heterotetrameric ANXA2 in intestinal epithelium to about 50% monomeric ANXA2 monomer in cultured fibroblasts (8Gerke V. Weber K. EMBO J. 1984; 3: 227-233Crossref PubMed Scopus (389) Google Scholar, 11Zokas L. Glenney Jr., J.R. J. Cell Biol. 1987; 105: 2111-2121Crossref PubMed Scopus (136) Google Scholar). ANXA2 consists of two functional domains. The aminoterminal regulatory domain (ATD) contains the amino-terminal 30 amino acid residues and incorporates two phosphorylation sites at Tyr-23 and Ser-25. In addition to the phosphorylation sites, the ATD also contains the site for interaction with the S100A10 dimer. The remaining CCD, encompassing residues 31–338, comprises the binding sites for Ca2+, phospholipid, heparin, and F-actin (reviewed by Refs. 1Gerke V. Moss S.E. Physiol. Rev. 2002; 82: 331-371Crossref PubMed Scopus (1628) Google Scholar, 2Filipenko N.R. Waisman D.M. Annexins: Biological Importance and Annexin-related Pathologies. Landes Bioscience, Georgetown, TX2003: 127-156Crossref Google Scholar, 3Waisman D.M. Mol. Cell Biochem. 1995; 149: 301-322Crossref PubMed Scopus (262) Google Scholar). The crystal structure of an amino-terminally truncated form of ANXA2 has been reported (12Burger A. Berendes R. Liemann S. Benz J. Hofmann A. Göttig P. Huber R. Gerke V. Thiel C. Römisch J. Weber K. J. Mol. Biol. 1996; 257: 839-847Crossref PubMed Scopus (110) Google Scholar). The protein is planar and curved with opposing convex and concave sides. The convex side faces the biological membrane and contains the Ca2+- and phospholipid-binding sites. The concave side faces the cytosol and contains both the amino and carboxyl termini. A multitude of intracellular functions have been suggested for ANXA2, including roles as a mediator of Ca2+-regulated exocytosis (13Sarafian T. Pradel L.A. Henry J.P. Aunis D. Bader M.F. J. Cell Biol. 1991; 114: 1135-1147Crossref PubMed Scopus (149) Google Scholar, 14Ali S.M. Burgoyne R.D. Cell Signal. 1990; 2: 265-276Crossref PubMed Scopus (33) Google Scholar, 15Ali S.M. Geisow M.J. Burgoyne R.D. Nature. 1989; 340: 313-315Crossref PubMed Scopus (235) Google Scholar, 16Burgoyne R.D. Nature. 1988; 331: 20Crossref PubMed Scopus (56) Google Scholar) or endocytosis (17Zeuschner D. Stoorvogel W. Gerke V. Eur. J. Cell Biol. 2001; 80: 499-507Crossref PubMed Scopus (39) Google Scholar, 18Emans N. Gorvel J.P. Walter C. Gerke V. Kellner R. Griffiths G. Gruenberg J. J. Cell Biol. 1993; 120: 1357-1369Crossref PubMed Scopus (229) Google Scholar, 19Harder T. Gerke V. J. Cell Biol. 1993; 123: 1119-1132Crossref PubMed Scopus (149) Google Scholar) as well as a role in modulating sarcolemmal phospholipid raft organization during smooth muscle cell contraction (20Babiychuk E.B. Monastyrskaya K. Burkhard F.C. Wray S. Draeger A. FASEB J. 2002; 16: 1177-1184Crossref PubMed Scopus (65) Google Scholar, 21Babiychuk E.B. Draeger A. J. Cell Biol. 2000; 150: 1113-1124Crossref PubMed Scopus (227) Google Scholar) and regulation of ion channels (22Okuse K. Malik-Hall M. Nature. 2002; PubMed Scopus Google Scholar). an ANXA2 has not been it is not reported in functions functions of the protein. of functions of ANXA2 has not as to the role that ANXA2 in vivo. The of ANXA2 is in transformed including or cells T. S. 1993; Google Scholar). the ANXA2 gene is and is by as and Cell 1990; PubMed Scopus Google Scholar). ANXA2 has also been reported in human M. P. K. J. M. Mol. Cell. Biol. 1990; PubMed Scopus Google J.K. 1993; PubMed Scopus Google high C. Davis R. M. Google K. M. T. K. A. S. 2001; 21: Google and N. J. 340: PubMed Scopus Google Scholar). of the ANXA2 gene is in both virally transformed cell lines and human it has been that up-regulated of ANXA2 ANXA2 to a in cellular a of intracellular it is to the role that up-regulation of ANXA2 have on cellular ANXA2 has been reported to two intracellular with the of the protein to the of the membrane and a S. R. K. Mol. Cell. Biol. 3: PubMed Scopus Google Scholar). The first that ANXA2 with RNA was a that to show that a of ANXA2 was with ribonucleoprotein in of both and transformed was also shown that ANXA2 from cultured cells with RNA and formed a ribonucleoprotein These also showed by that about of the total cellular ANXA2 was with the EMBO J. 2: PubMed Scopus Google Scholar). studies showed that ANXA2 bind to acid as P. Waisman D.M. Proc. Natl. Acad. Sci. U. S. A. 1990; PubMed Scopus Google Scholar) or V. M. N. PubMed Scopus Google Scholar). studies have identified nuclear ANXA2 in of and as of a complex that (6Jindal H.K. Chaney W.G. Anderson C.W. Davis R.G. Vishwanatha J.K. J. Biol. Chem. 1991; 266: 5169-5176Abstract Full Text PDF PubMed Google Scholar, J.K. H.K. Davis R.G. J. Cell Sci. PubMed Google Scholar). ANXA2 was also shown to with mRNA A. Biochem. J. 2000; PubMed Scopus Google Scholar). it was shown that ANXA2 a nuclear and it was that ANXA2 the is J. Cell Sci. 2001; 114: PubMed Google Scholar). In the present we have examined HeLa cell for the presence of we that proteins bound to an ANXA2 affinity and was by with A. also show that in the presence of Ca2+, ANXA2 binds to homopolymers with a high affinity for poly(G) and in a Subsequently, we show that ANXA2 is an RNA-binding protein that a messenger ribonucleoprotein identify c-myc RNA as a component of the complex and show that ANXA2 binds directly to c-myc mRNA. the of ANXA2 in a cell of protein in an in both ANXA2 and c-Myc protein. studies identify ANXA2 as a RNA-binding protein that the of c-myc RNA. Cell and Cell and cells from the and at in in 10% and The for ANXA2 and S100A10 and or The c-myc was a from was used as in the to of the human cell with the and cells with and cell lines by ANXA2 and S100A10 protein cells with with and by at for 10 at cells by cells in of 10 and the a by in a on for 10 a was by the cell for 10 at protein by and cell in of was with of or and of protein for at ANXA2 from or to the and the for at by the addition of for an The complexes three and in for analysis or with for RNA proteins in on to and substrate from the A2 and and Cell RNA RNA and The ANXA2 or complexes three with and to a of with The with of and with of for 30 at The RNA was with of by as a acid The RNA was to with and at The bound RNA was RNA and cytidine as G. PubMed Scopus Google Scholar). of the RNA was with of of of pCp, and of RNA in a of and for at by and as of the was by of acid analysis of was by of of RNA on a The was and the RNA was by analysis of the bound RNA was the the at the of the c-myc mRNA as E. T. D.M. S.M. S. Mol. Cell. Biol. 1995; PubMed Scopus Google the Sucrose of Cell gradient was as M. A. A. S. C. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). from cells in a gradient in to by for at in a by a gradient of gradient was for with and as of cell to was as with a V. K. L. C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Cell in of was with a of and for 30 at The three with in of and for ANXA2 by as ANXA2 binding to of ANXA2 was to of in of binding analysis was as by or by with ANXA2 and at to of to the was by of with 10 of the of ANXA2 and protein binding 10 of cell was first with of the in the presence of or for at was with of the ANXA2 or affinity for at The three with 10 of and the bound proteins for 10 in for for annexin of the proteins on and with the of cellular RNA or in binding of the proteins to the ANXA2 affinity the cell at with or A for 30 the the cell in the presence of with the by with the ANXA2 affinity proteins as by and and an was on a The and with and the from the and was on a high and a a identified from the and the and of as well as the the for ANXA2 by and have been J. P. Henry J.P. 2000; PubMed Scopus Google Scholar). The of the S100A10 protein was and the by the transformation of the the S. by The and of the was as J. P. Henry J.P. 2000; PubMed Scopus Google with only to of annexin and in the of of ANXA2 and ANXA2 heterotetramer the The isolated proteins in and and at c-myc was and in with with RNA by in with the c-myc mRNA was with of with or c-myc and and The binding was in a 10 and of The at 30 for 30 which with on for of 30 with a with of A at for and by heterotetramer was to a in a the in 10 at and a of 30 A cell was used as a for the of the to the the was with an of 10 was by the at poly(G) to at by analysis the to the = is the at C is the of and is the ANXA2 a a first in of the of ANXA2, we to intracellular proteins that with In to binding we with ANXA2 or a Annexin which has and to ANXA2, was also to the as a Cell from HeLa or cells first with by to the ANXA2 or These cell of of HeLa cells have an of ANXA2, cells have ANXA2 by not the annexins are to Ca2+ to bind to cellular the cell with the affinity in the presence or of of the binding the proteins bound to the by in by on that cellular proteins with the ANXA2 These cellular proteins not with the or the affinity and the of proteins with the ANXA2 required is to that cell as not that the bound not high of ANXA2 it to bind to ANXA2 established that ANXA2 binds to a of cellular proteins in a and Ca2+-dependent the and and the by A of the is shown in we that of the proteins identified as proteins proteins or proteins that are to with cellular RNA. the major proteins that bound to the ANXA2 affinity M. PubMed Scopus Google protein A. Biochem. Cell Biol. 1995; PubMed Scopus Google protein M. S. G. 1989; PubMed Scopus Google protein N. T. S. Davis E. N. T. PubMed Scopus Google Scholar) and protein Mol. Cell. Biol. PubMed Scopus Google Scholar). suggested that RNA or RNA-binding proteins with bound to Annexin A2 subunit proteins in a between two the ANXA2 affinity binding with cell with or shown in the between ANXA2 and the cellular proteins was by with A. In the of the cellular with or not the of cellular proteins bound to the ANXA2 affinity These that ANXA2 with cellular proteins to form a ribonucleoprotein complex and that RNA is required for the interaction of ANXA2 with cellular binding ANXA2 RNA in interaction of ANXA2 with RNA was by HeLa cell with RNA has been used to the RNA binding of other RNA-binding proteins V. K. L. C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, G. Mol. Cell Biol. 1991; PubMed Scopus Google Scholar, G. Mol. Cell Biol. 1988; PubMed Scopus Google Scholar). HeLa cell with the RNA and bound proteins and by an ANXA2 that ANXA2 bound to and that interaction was on Ca2+ at the bound proteins with a to the confirmed the presence of the S100A10 binding not that of the ANXA2 bound to poly(G) was to S100A10 as the the interaction of ANXA2 with S100A10 binding not to with used a of binding to the interaction of HeLa cell ANXA2 with The binding of the ANXA2 to poly(G) was in heparin and in to C and ANXA2 bound to poly(G) in the presence of as high as as a In to the proteins that bound to the the protein from HeLa cell was also by and that a protein was the protein in identified protein as ANXA2, that ANXA2 was the major protein in the HeLa cell The of complexes suggested that ANXA2 directly interacts with RNA or other between ANXA2 was for RNA binding the RNA used the heterotetrameric form of ANXA2 for it is the form of the protein in cell shown in heterotetrameric ANXA2 showed binding to poly(G) with binding to poly(A), poly(C), or poly(U). with the monomeric form of ANXA2 not also the of the binding by with ANXA2 was with the poly(G) in the presence of a of that the binding of ANXA2 to the poly(G) was by the poly(G) not by poly(A), poly(C), or to the interaction of HeLa cell ANXA2 with poly(G) the binding of ANXA2 to poly(G) was not by or heparin and was in the presence of not In addition to the the interaction of poly(G) homopolymers with the ANXA2 heterotetramer was two ANXA2 was to a and the binding to the RNA homopolymers was examined by the ANXA2 bound only to These established that ANXA2 bound and with high affinity (Kd of 60 nm) to poly(G) only the binding of poly(G) resulted in a in ANXA2 as by not of the of poly(G) ANXA2 the RNA-binding the ANXA2 established that poly(G) and ANXA2 form a and was both subunits of ANXA2 heterotetramer to poly(G) in ANXA2 binds to poly(G) it is as the heterotetramer or as a In the S100A10 subunit not bind the ANXA2 monomer consists of an ATD, which comprises the first 30 amino acid residues of the and a CCD composed of the remaining residues Glenney J.R. Biochem. J. 1987; PubMed Scopus Google Scholar). The ATD is from the by established that the ANXA2 monomer contains the RNA-binding the RNA binding of the CCD was with the ANXA2 monomer to the of ANXA2 for binding to is shown in both the monomer and the CCD by poly(G) that the poly(G) binding site is the CCD of was it suggested that the CCD, which is the a RNA-binding that was unique to of a tissue annexin annexins S. R. Waisman D.M. 1990; PubMed Scopus Google Scholar) with resulted in the binding of only a single which was confirmed by to ANXA2 a not with of the annexins in the tissue These established that the RNA binding of ANXA2 was not a by other of the annexin family of was acid binding a of the annexin ANXA2 an in ANXA2 with RNA in vivo, we ANXA2 from HeLa cell and the of the a immunoprecipitates of also The of the was confirmed by The RNA was isolated from the immunoprecipitates and by the G. PubMed Scopus Google Scholar). shown in the ANXA2 isolated from HeLa cell was with and the was not an immunoprecipitates that immunoprecipitates not amounts of that the the used for the for the of RNA with the that ANXA2 formed complexes in vivo, we HeLa cell on and the ANXA2 by a for protein was used as a for and polyribosomes. The of the protein was by for as a substrate not shown in ANXA2 with the in the of the In of the HeLa with A resulted in the of ANXA2 in the protein showed that ANXA2 formed an complex and that RNA was for the of of c-myc mRNA as a of the complex on the gradient was and with the ANXA2 RNA was isolated from the and to c-Myc is for Src transformation T. D. W. R. T. R. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar) and ANXA2 is in we the that ANXA2 a role in the regulation of c-myc mRNA. shown in we the presence of c-myc mRNA in the RNA isolated from the ANXA2 In we not mRNA in the immunoprecipitates not to mRNA that ANXA2 is not a RNA-binding protein binds to a of cellular These that ANXA2 is of an complex in that contains c-myc mRNA and other RNA ANXA2 to c-myc presence of c-myc RNA in the complex to the direct interaction of ANXA2 with c-myc mRNA or to the interaction of ANXA2 with a component of between we a with ANXA2 and c-myc mRNA. shown in ANXA2 binds directly to c-myc mRNA. the interaction between ANXA2 and c-myc RNA was by poly(G) or c-myc mRNA not by In the interaction between ANXA2 and c-myc mRNA was Ca2+-dependent the of the interaction of c-myc mRNA with ANXA2, we an RNA and that RNA not with the c-myc for binding to ANXA2 that the interaction between ANXA2 and c-myc mRNA is and of ANXA2 cellular of c-Myc protein. of the ANXA2 S100A10 and c-Myc protein in cell lines and The of c-Myc protein by of ANXA2 with up-regulation of c-Myc protein. LNCaP cells with and by and and cell lines cell for ANXA2 and S100A10 and cells by for cellular of ANXA2 and c-Myc is as a of ANXA2 c-Myc form of ANXA2 in cultured cells is to S100A10 binding as a studies have established that ANXA2 is a protein in human cell lines as and ANXA2 and S100A10 binding are not present in the human LNCaP cell A. P. S. J. 2001; Google Scholar). examined the c-Myc protein in three cell shown in the human cell is of ANXA2 and also has of c-Myc protein with the and cell lines the between ANXA2 and we the LNCaP cells with the gene for both ANXA2 and S100A10 binding and cell lines both ANXA2 and S100A10 cell both shown in LNCaP cell lines ANXA2 have up-regulated of c-Myc protein with the cells In the we that ANXA2 is a unique RNA-binding protein. The of the well established RNA-binding from the of ANXA2 as well as the of the protein for poly(G) that ANXA2 a unique RNA-binding also that the binding of poly(G) to ANXA2 is on is the first of a Ca2+-dependent RNA-binding protein. that ANXA2 is a unique RNA-binding protein. RNA-binding have been identified (reviewed in G. PubMed Scopus Google Scholar). These the the the the the RNA-binding and the The of from ANXA2 that the RNA-binding domain of protein is unique the RNA-binding of the annexins for RNA binding only ANXA2 bound to RNA it is that the presence of an RNA-binding domain in ANXA2 is unique to the annexin family of binding studies have shown that ANXA2 is a affinity Ca2+-binding protein that binds Ca2+ with a of about as shown in the interaction of the protein with RNA with a of about 10 that the interaction of ANXA2 with RNA a in a in the of the Ca2+-binding sites from affinity to higher affinity Ca2+-binding sites. of a Ca2+-dependent in ANXA2 upon RNA as by not is with we to the RNA-binding site of ANXA2, we that the RNA-binding domain of ANXA2 is in the carboxyl domain of the protein. c-Myc is a nuclear that cell and cellular c-Myc at the by as a of gene or The of c-myc mRNA is cells or c-myc mRNA is in the and the other is in the A RNA-binding the binds to the c-myc in and it from and the mRNA R.D. J. PubMed Scopus Google Scholar). The also a role in the regulation of the interaction of the binding with the on the c-myc mRNA by M.J. M. PubMed Scopus Google Scholar). In we have used an to show that ANXA2 a complex in HeLa and we identify species of mRNA in complex as c-myc mRNA we show that ANXA2 binds directly to c-myc mRNA the binding site on c-myc mRNA was not identified in it was that the interaction of ANXA2 with c-myc mRNA in the up-regulation of c-Myc protein that the binding of ANXA2 to c-myc mRNA have an role in the regulation of c-myc mRNA. In the RNA-binding proteins a of functions including mRNA and the and of mRNA In the RNA-binding proteins in the of mRNA in the (reviewed in G. N. Rev. Mol. Cell. Biol. 2002; 3: PubMed Scopus Google Scholar). that ANXA2 a complex in and not with subunits or it is that ANXA2 not directly with the directly interacts with mRNA in the of a that ANXA2 in the up-regulation of c-Myc protein the that ANXA2 c-myc mRNA or studies that the of LNCaP cells with the ANXA2 gene in the of ANXA2 protein and an of c-Myc protein are with a in which ANXA2 a role in the regulation of c-myc mRNA during cellular c-myc is up-regulated in of including C. C. R. U. 2002; PubMed Scopus Google Scholar, P. Jr., 3: PubMed Scopus Google D. E. N. R. D. Google and J. E. Full Text Full Text PDF PubMed Scopus Google Scholar). the of the ANXA2 gene is in both virally transformed cell lines and human tumors. the of ANXA2 is in transformed including or cells T. S. 1993; Google Scholar). the ANXA2 gene is and is by as and Cell 1990; PubMed Scopus Google Scholar). ANXA2 has also been reported in human M. P. K. J. M. Mol. Cell. Biol. 1990; PubMed Scopus Google J.K. 1993; PubMed Scopus Google high C. Davis R. M. Google K. M. T. K. A. S. 2001; 21: Google and N. J. 340: PubMed Scopus Google Scholar). or not ANXA2 a role in the regulation of c-myc during is also to that the Ca2+-dependent regulation of c-myc has been reported in cells J. 1990; Google Scholar). the up-regulation of ANXA2 or by in Ca2+ have the to a role in the regulation of c-myc. In that ANXA2 is a RNA-binding protein that binds directly to c-myc mRNA and c-Myc protein. a between the Ca2+ messenger and the regulation of c-myc mRNA. are to and of for also and for the of the we for the and of for the c-myc are also to both and for for of ANXA2 and S100A10 in S.

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