Heterogeneous Nuclear Ribonucleoprotein F/H Proteins Modulate the Alternative Splicing of the Apoptotic Mediator Bcl-x

Bcl-x is a member of the Bcl-2 family of proteins that are key regulators of apoptosis. The Bcl-x pre-mRNA is alternatively spliced to yield Bcl-xS and Bcl-xL, two isoforms that have been associated, respectively, with the promotion and the prevention of apoptosis. We have investigated some of the elements and factors involved in the production of these two splice variants. Deletion mutagenesis using a human Bcl-x minigene identifies two regions in exon 2 that modulate Bcl-x 5′-splice site selection in human HeLa cells. One region (B3) is located upstream of the Bcl-xL 5′-splice site and enforces Bcl-xL production in cells and splicing extracts. The other region (B2) is located immediately downstream of the 5′-splice site of Bcl-xS and favors Bcl-xS production in vivo and in vitro. A 30-nucleotide G-rich element (B2G) is responsible for the activity of the B2 element. We show that recombinant heterogeneous nuclear ribonucleoprotein (hnRNP) F and H proteins bind to B2G, and mutating the G stretches abolishes binding. Moreover, the addition of hnRNP F to a HeLa extract improved the production of the Bcl-xS variant in a manner that was dependent on the integrity of the G stretches in B2G. Consistent with the in vitro results, small interfering RNA-mediated RNA interference targeting hnRNP F and H decreased the Bcl-xS/Bcl-xL ratio of plasmid-derived and endogenously produced Bcl-x transcripts. Our results document a positive role for the hnRNP F/H proteins in the production of the proapoptotic regulator Bcl-xS. Bcl-x is a member of the Bcl-2 family of proteins that are key regulators of apoptosis. The Bcl-x pre-mRNA is alternatively spliced to yield Bcl-xS and Bcl-xL, two isoforms that have been associated, respectively, with the promotion and the prevention of apoptosis. We have investigated some of the elements and factors involved in the production of these two splice variants. Deletion mutagenesis using a human Bcl-x minigene identifies two regions in exon 2 that modulate Bcl-x 5′-splice site selection in human HeLa cells. One region (B3) is located upstream of the Bcl-xL 5′-splice site and enforces Bcl-xL production in cells and splicing extracts. The other region (B2) is located immediately downstream of the 5′-splice site of Bcl-xS and favors Bcl-xS production in vivo and in vitro. A 30-nucleotide G-rich element (B2G) is responsible for the activity of the B2 element. We show that recombinant heterogeneous nuclear ribonucleoprotein (hnRNP) F and H proteins bind to B2G, and mutating the G stretches abolishes binding. Moreover, the addition of hnRNP F to a HeLa extract improved the production of the Bcl-xS variant in a manner that was dependent on the integrity of the G stretches in B2G. Consistent with the in vitro results, small interfering RNA-mediated RNA interference targeting hnRNP F and H decreased the Bcl-xS/Bcl-xL ratio of plasmid-derived and endogenously produced Bcl-x transcripts. Our results document a positive role for the hnRNP F/H proteins in the production of the proapoptotic regulator Bcl-xS. Alternative splicing is a powerful generator of proteomic diversity. It is estimated that as much as 74% of all human genes may use alternative splicing as part of their expression program (1Johnson J.M. Castle J. Garrett-Engele P. Kan Z. Loerch P.M. Armour C.D. Santos R. Schadt E.E. Stoughton R. Shoemaker D.D. Science. 2003; 302: 2141-2144Crossref PubMed Scopus (1196) Google Scholar). In the most remarkable example to date, the Drosophila DSCAM gene can potentially yield more than 38,000 different isoforms by alternative splicing (2Schmucker D. Clemens J.C. Shu H. Worby C.A. Xiao J. Muda M. Dixon J.E. Zipursky S.L. Cell. 2000; 101: 671-684Abstract Full Text Full Text PDF PubMed Scopus (827) Google Scholar). Alternative splicing has the potential to alter protein activity in many important ways. In some cases, the inclusion of sequences carrying a stop codon can trigger non-sense-mediated RNA decay, thereby down-regulating protein expression (3Lewis B.P. Green R.E. Brenner S.E. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 189-192Crossref PubMed Scopus (772) Google Scholar, 4Wollerton M.C. Gooding C. Wagner E.J. Garcia-Blanco M.A. Smith C.W. Mol. Cell. 2004; 13: 91-100Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar). In other instances, alternative splicing yields protein variants with drastically different and sometimes antagonistic properties. This is the case with the Bcl-x pre-mRNA, which experiences alternative 5′-splice site utilization to produce the anti-apoptotic Bcl-xL protein or the proapoptotic Bcl-xS isoform (5Boise L.H. Gonzalez-Garcia M. Postema C.E. Ding L. Lindsten T. Turka L.A. Mao X. Nunez G. Thompson C.B. Cell. 1993; 74: 597-608Abstract Full Text PDF PubMed Scopus (2933) Google Scholar). Bcl-x is a member of the large bcl-2 family of apoptotic genes. Bcl-x proteins modulate mitochondrial protein release, an event associated with the induction of programmed cell death. In a number of cancers and cancer cell lines, the expression of the anti-apoptotic protein Bcl-xL is increased, and the ratio of the splice variants is frequently shifted to favor production of Bcl-xL (6Tu Y. Renner S. Xu F. Fleishman A. Taylor J. Weisz J. Vescio R. Rettig M. Berenson J. Krajewski S. Reed J.C. Lichtenstein A. Cancer Res. 1998; 58: 256-262PubMed Google Scholar, 7Reeve J.G. Xiong J. Morgan J. Bleehen N.M. Br. J. Cancer. 1996; 73: 1193-1200Crossref PubMed Scopus (91) Google Scholar, 8Olopade O.I. Adeyanju M.O. Safa A.R. Hagos F. Mick R. Thompson C.B. Recant W.M. Cancer J. Sci. Am. 1997; 3: 230-237PubMed Google Scholar, 9Krajewska M. Krajewski S. 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Although perturbations in alternative splicing have been observed in neoplasia and metastasis (16Philips A.V. Cooper T.A. Cell Mol. Life Sci. 2000; 57: 235-249Crossref PubMed Scopus (109) Google Scholar, 17Nissim-Rafinia M. Kerem B. Trends Genet. 2002; 18: 123-127Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 18Wu J.Y. Tang H. Havlioglu N. Jeanteur P. Regulation of Alternative Splicing. 31. Springer-Verlag, Berlin Heidelberg2003: 153-185Google Scholar), the identity of the factors that elicit these cancer-specific changes One has that the to metastasis in a of with an in the of a family of proteins involved in and alternative splicing F. D. Oncogene. 1999; 18: PubMed Scopus Google Scholar). Although changes in protein expression with changes in splicing F. D. Oncogene. 1999; 18: PubMed Scopus Google Scholar), in proteins are to of in the expression of splicing regulators neoplasia and of the of is by elements by the hnRNP heterogeneous nuclear small interfering targeting hnRNP targeting hnRNP F and small nuclear protein J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), and protein expression is increased in Cancer Res. 2000; Google Scholar). The with Bcl-x and is the that Bcl-x alternative splicing in and cancer cells. A in human cells that can the ratio of Bcl-x isoforms in favor of Bcl-xS C.E. K. R.E. B. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The activity of is by protein which are to alter the of proteins J.E. J. 13: PubMed Scopus Google Scholar). elements the Bcl-xS 5′-splice a and a are for and use of the Bcl-xS site A. A. P. C.E. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). the of factors in the of Bcl-x alternative splicing to We have to the elements that the alternative splicing of human Our identifies two elements that the splicing ratio in human HeLa cells. Although the element Bcl-xL the B2 element Bcl-xS We show that hnRNP F/H proteins the activity of the B2 element in vitro and in human Bcl-x gene was The minigene for in vitro splicing was by the of the of the Bcl-x in the using and This was in the site to The of Bcl-x was the using and and the was in the site to was produced by with with and with The Bcl-x was the and upstream of the Bcl-x gene cells. with and a that was with and the and site to yield was produced using the that the upstream was was produced by a on using and The was with and and for the in was using the using and The was with and and for the of The and produced by the of the a by and was in with and was produced a using and The was for the in was produced by a using and produced by an and treated with The of to in the was and in and with was with and treated with The was and with and treated with mutagenesis was to and two using the A was with the and and a with and The two as for a using the and This the was with and and for the of and and to their and of HeLa cells in and 2 cells in using of and of using the two of using a The sequences in hnRNP F and F/H and The the the was using RNA was the using to the The RNA was treated with for by a of of the RNA was with the for using for the and for plasmid-derived of these was for in a and of The for and and and for plasmid-derived ratio the number of in was by the on an The was and the of the In for in vitro the by using and and on and using the to the for in vitro splicing using RNA in the of a and Life RNA was as B. RNA A Scholar). In of the for 2 in HeLa nuclear Res. PubMed Scopus Google A.R. T. B. Green Cell. Full Text PDF PubMed Scopus Google Scholar). RNA was in The was using the of of pre-mRNA using with the and was for The was by in the of Life using the for for for for the in vivo and for and a for using and was on an as of the hnRNP F/H the hnRNP F or hnRNP H by of using and and the the A expression was to the recombinant The proteins using cells by and with and by using the and the the The with the and with a and with and and and the with the for in of and of splicing 2 of in the or the of hnRNP of of was the on a in cell by in and proteins or recombinant proteins a and on a was to using F or H a of and with The was a to in a toward the of elements involved in the of 5′-splice site selection in human the of in a Bcl-x minigene in the HeLa cell The Bcl-x minigene was by the upstream of the human gene with downstream of which is than was for the of region sequences that are human and The of 2 are and are to produce the isoform H. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). in HeLa cells, and the of Bcl-xS and Bcl-xL isoforms was estimated by with of the to plasmid-derived sequences In to Bcl-x which the Bcl-xL variant in HeLa cells the minigene more of the Bcl-xS variant Although the Bcl-x splicing the minigene the splicing of the with of with the of sequences in the minigene that alter the The of exon and the splicing ratio minigene the of exon 2 alter the ratio In different the Bcl-xS/Bcl-xL ratio and the ratio 2 and in the Bcl-x splicing ratio are of the of the cells the of the We two different in a different on the of the Bcl-x The the B2 which a downstream the 5′-splice site of Bcl-xS to to the Bcl-xS splice The of B2 the production of Bcl-xS the of an element that is for the use of the 5′-splice site of Bcl-xS. In contrast, the of the which is located upstream of the 5′-splice site of Bcl-xL to to the Bcl-xL splice the production of Bcl-xL The results to a role for regions in the ratio of the Bcl-x the the of the Bcl-xL the of Bcl-xS is that the alter the of the plasmid-derived Bcl-x more the of the B2 and elements on splice site splicing in a HeLa nuclear and produced and in splicing for 2 Although the of splicing for these large was of the of splicing in splicing was by the production of large some on a to the produced the pre-mRNA The results that pre-mRNA was spliced to produce Bcl-xL Although the Bcl-xS/Bcl-xL splicing ratio of pre-mRNA in different and in different HeLa produced more of the Bcl-xL isoform In contrast, the was associated with a in the of the Bcl-xL with the in vivo splicing of The B2 the in vivo in Bcl-xS that the 5′-splice site of Bcl-xS in the an antisense oligonucleotide complementary to the 5′-splice site of Bcl-xL was to splicing When pre-mRNA was with of oligonucleotide Bcl-xL production decreased to favor Bcl-xS The oligonucleotide with the pre-mRNA the production of the was the of The 5′-splice site of Bcl-xS was the 5′-splice site of Bcl-xL in the of a the B2 region the 5′-splice site of Bcl-xS. Moreover, the of the on in vitro and in vivo Bcl-x splicing that the B2 and elements modulate 5′-splice site selection than of the B2 element (B2G) Bcl-xS of the region the Bcl-xS and Bcl-xL 5′-splice and of the in The of the Bcl-x 5′-splice is The sequences of the B2 and elements are and The sequences in and are in vitro splicing of the and in HeLa nuclear for 2 RNA was and to with a of The of the Bcl-xS and Bcl-xL is and the ratio of the is the an on a splicing pre-mRNA that was on We the of the on alternative splicing by the of more elements in the of the Bcl-xS or Bcl-xL 5′-splice the B2 and elements for sequences of two different as a for B2 the in Bcl-xS production in 2 with and in and the element for a of the Bcl-xL production results that the B2 and regions sequences that 5′-splice site A of B2 by hnRNP F and H in more the identity of the sequences and factors in the of 5′-splice site selection in on the B2 element located immediately downstream of the Bcl-xS 5′-splice produced of the or of B2 and an in vitro splicing that an in Bcl-xS the Bcl-xS was and This that the 30-nucleotide located and (B2G) the toward the use of the Bcl-xS 5′-splice Consistent with a pre-mRNA carrying a of the element Bcl-xS a splicing to The to region the G-rich sequences have been as for the hnRNP F and H proteins S. A. L. C. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, N. C.W. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar, C.D. R. 1999; 13: PubMed Scopus Google Scholar, M. J. 2002; PubMed Scopus Google Scholar, M. R. G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, M. L. D. M. Res. 2004; PubMed Scopus Google Scholar). the of hnRNP F and H proteins to bind to by a RNA oligonucleotide carrying the to with recombinant hnRNP F or H produced cells a a produced protein In a hnRNP F and H the of the of and In contrast, the protein the of the RNA The of by hnRNP F and H was by of The addition of a of RNA the of the and was observed a of a RNA oligonucleotide was and the role of hnRNP F/H proteins in the activity of the B2 the of mutating the G-rich stretches in the We produced two the a to in the G the the the and the G the of hnRNP F and hnRNP as by on RNA a of the the of a the RNA with hnRNP that mutating the G in hnRNP F The for their on Bcl-x splice site selection in vitro. In the of the B2 Bcl-xS and Our results that the two G stretches in are important for hnRNP F and H binding. In the of the B2 element mutating the G is to the element. The of located downstream of the element may mutating G in is to Bcl-xS the that two in are important for hnRNP F/H and Bcl-xS splicing is with the that the hnRNP F/H proteins Bcl-xS production by to the G-rich elements in B2G. hnRNP F and H to the of Bcl-xS in the role of hnRNP F/H proteins in Bcl-x splicing the activity of the recombinant hnRNP F and H proteins on Bcl-x splicing in vitro. The addition of recombinant hnRNP F to a splicing pre-mRNA a toward the production of the Bcl-xS isoform The of recombinant hnRNP F to was to the of hnRNP F protein in the nuclear extract hnRNP H improved Bcl-xS splicing In to hnRNP F and the addition of the production of Bcl-xL The splicing by the addition of hnRNP F a element hnRNP F to a the pre-mRNA Bcl-xS production and Consistent with the that the Bcl-x splicing the addition of recombinant hnRNP F to the pre-mRNA improved the production of Bcl-xS and results that the of hnRNP F or hnRNP H to is important for the activity of the B2 element. hnRNP F/H Bcl-xS in the hnRNP F/H proteins the splicing of Bcl-x in on RNA interference to the levels of hnRNP F and H proteins in HeLa cells. targeting hnRNP F or targeting hnRNP F and hnRNP H two a and a of minigene was to the in hnRNP F and H When with the protein cells that been with or a in hnRNP F protein the of hnRNP and the in hnRNP H by was to the splicing of plasmid-derived Bcl-x these The in hnRNP F expression was associated with a toward the production of the Bcl-xL isoform A more important was observed hnRNP F and hnRNP H by RNA interference The of a of hnRNP F/H was by the Bcl-xS/Bcl-xL ratio in RNA interference in In a different the of the RNA interference by using a of two with to the hnRNP F and H to Although the of on hnRNP F and H expression was important in and a in Bcl-xS was observed In contrast, the of hnRNP F or hnRNP H and and in the Bcl-x splicing ratio was observed the in the and of the the of hnRNP F/H in HeLa cells Bcl-x RNA interference using and in the of a the proteins and the in the of hnRNP F and H proteins was by that a toward Bcl-xL, and was with the results of the RNA interference that a in the levels of hnRNP F and hnRNP H proteins the use of the 5′-splice site in plasmid-derived and Bcl-x transcripts. The of Bcl-x alternative splicing is of to the apoptotic and is to In have two regions in exon 2 of Bcl-x that can modulate splicing in vitro and in The B2 and elements are located in the 5′-splice of Bcl-xS and Bcl-xL, the production of the Bcl-xS and Bcl-xL The activity of the B2 element is by a B2G, located downstream of the Bcl-xS Although the of can the of a of the B2 element and Bcl-xS sequences downstream of to have some A more mutagenesis targeting these sequences to the of the of the B2 element. A has two elements and that elicit the toward Bcl-xS in the human cell C.E. K. R.E. B. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). elements to the Bcl-xS/Bcl-xL ratio in cells. Although have the of in the of was the of sequences downstream of to to the 5′-splice site of In to cells, the that the production of Bcl-xS in a HeLa extract The of Bcl-x splicing to and exon 2 may many elements that Bcl-x splicing to to a of in The element that have in splicing to the Bcl-xL 5′-splice on the by to Bcl-x We have a different element in exon 2 that a splicing in cells, in HeLa cells, in to the apoptotic T. and B. Bcl-xS was the produced the Bcl-x expression in HeLa cells favors the Bcl-xL This that the role of is as in endogenously produced Bcl-x and that the minigene that are to Bcl-xS Bcl-xL The splicing and Bcl-x can the Bcl-x gene in HeLa cells may that splicing plasmid-derived Bcl-x may to the a that to the of with an on the Bcl-xS/Bcl-xL the of most of the 2 in the minigene may alter splicing the the large of 2 that the 5′-splice of exon 2 and the site of exon more to than for an a may the activity of elements that by to more that Bcl-xL is the that alter the of the RNA may have an on Bcl-x splice site It to by Bcl-x is spliced the of is Although alternative in the Bcl-x gene alternative splicing A. J.L. M. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, Gonzalez-Garcia M. D. L. N. S. M.F. Nunez G. J. 1997; Google Scholar), is these changes are by different or by the of elements located the of some of the hnRNP F/H and the of in 30-nucleotide element involved in the use of the Bcl-xS 5′-splice site has the the two G stretches the activity of the B2 element. have been as for of the hnRNP family of proteins S. A. L. C. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, N. C.W. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar, C.D. R. 1999; 13: PubMed Scopus Google Scholar, M. J. 2002; PubMed Scopus Google Scholar, M. R. G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). We have that the recombinant hnRNP F and hnRNP H proteins can with the RNA and that in a G Moreover, recombinant hnRNP F and hnRNP H proteins can Bcl-xS splicing in and by hnRNP F is observed are hnRNP F expression by RNA interference shifted the in vivo splicing of plasmid-derived toward A in hnRNP H Bcl-x splicing more than the of hnRNP F Moreover, the of hnRNP F and hnRNP H expression Bcl-xS hnRNP F and hnRNP H may have activity with to Bcl-x alternative the that proteins may for the activity of the element. The hnRNP F and H proteins have been to with a G-rich located in the that favors exon inclusion in the pre-mRNA in cells N. C.W. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar, H. 1995; PubMed Scopus Google Scholar). Although hnRNP H can with hnRNP F and is for exon hnRNP by recombinant hnRNP F N. C.W. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar). Moreover, hnRNP F bind to the RNA element M. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). that hnRNP F and hnRNP H bind to the Bcl-x element with hnRNP F and hnRNP H may as for Bcl-x splicing Our the or of hnRNP F and of Bcl-x The by which hnRNP F/H proteins modulate Bcl-x splicing The of to the 5′-splice site of Bcl-xS that hnRNP F/H the 5′-splice site of Bcl-xS. the of hnRNP H to an element in exon of the human pre-mRNA M. J. 2002; PubMed Scopus Google Scholar). the F/H the of to the 5′-splice site of activity of which to 5′-splice P. N. C. S. B. P. J. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, C. F. D. L. R. J. F. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, F. C. L. M.C. J. R. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar), the of P. C. B. J. J. 2002; PubMed Scopus Google Scholar), and favors the production of the proapoptotic isoform of the cell P. J. 2001; PubMed Scopus Google Scholar). The of Bcl-xS and Bcl-xL in apoptosis that in the levels of hnRNP F and hnRNP H proteins may cells to apoptotic The hnRNP F and H proteins important in in that hnRNP F is more in the than in the the is for hnRNP H and the hnRNP protein B. U. H. Cell Res. 2004; PubMed Scopus Google Scholar). The nuclear of hnRNP H is increased in as and hnRNP F expression high in in B. U. H. Cell Res. 2004; PubMed Scopus Google Scholar). Although these are in with the production of Bcl-xS that in the ratio the Bcl-xS and Bcl-xL isoforms by the of elements and may modulate the activity of hnRNP F/H Although the of in the activity of hnRNP F/H proteins has been in the that apoptotic cells an increased in hnRNP H R. G. A. 2004; PubMed Scopus Google is with the hnRNP F/H and apoptosis. The of to the activity of hnRNP F/H and Bcl-x splicing We and for their We are to for the of nuclear and the to for recombinant and to for the hnRNP F and H and

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