Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The RNA-binding protein La contributes to cell proliferation and CCND1 expression

Oncogene volume 30, pages 434–444 (2011)Cite this article

Subjects

Abstract

The La protein is an essential RNA-binding protein implicated in different aspects of RNA metabolism. Herein, we report that small interfering (siRNA)-mediated La depletion reduces cell proliferation of different cell lines concomitant with a reduction in cyclin D1 (CCND1) protein. To exclude off-target effects we demonstrate that exogenous La expression in La-depleted cells restores cell proliferation and CCND1 protein levels. In contrast, proliferation of immortalized CCND1 knockout cells is not affected by La depletion, supporting a functional coherence between La, CCND1 and proliferation. Furthermore, we document by reversible in vivo crosslinking and ribonucleoprotein (RNP) immunoprecipitation an association of the La protein with CCND1 messengerRNA and that CCND1 internal ribosome entry site (IRES)-dependent translation is modulated by La protein level within the cell. In addition, we show elevated La protein expression in cervical cancer tissue and its correlation with aberrant CCND1 protein levels in cervical tumor tissue lysates. In conclusion, this study establishes a role of La in cell proliferation and CCND1 expression and demonstrates for the first time an overexpression of the RNA-binding protein La in solid tumors.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

Abbreviations

CCND1:

cyclin D1

con:

control

FACS:

fluorescence-activated cell sorting

GAPDH:

glyceraldehyde 3-phosphate dehydrogenase

GFP:

green fluorescent protein

MEF:

mouse embryonic fibroblasts

PARP:

poly (ADP-ribose) polymerase

siRNA:

small interfering RNA

TMA:

tissue micro array

XIAP:

X-linked inhibitor of apoptosis

IRES:

internal ribosome entry site

References

  • Al-Ejeh F, Darby JM, Brown MP . (2007). The La autoantigen is a malignancy-associated cell death target that is induced by DNA-damaging drugs. Clin Cancer Res 13: 5509s–5518s.

    Article  CAS  PubMed  Google Scholar 

  • Albanese C, D′Amico M, Reutens AT, Fu M, Watanabe G, Lee RJ et al. (1999). Activation of the cyclin D1 gene by the E1A-associated protein p300 through AP-1 inhibits cellular apoptosis. J Biol Chem 274: 34186–34195.

    Article  CAS  PubMed  Google Scholar 

  • Ali N, Pruijn GJ, Kenan DJ, Keene JD, Siddiqui A . (2000). Human La antigen is required for the hepatitis C virus internal ribosome entry site-mediated translation. J Biol Chem 275: 27531–27540.

    CAS  PubMed  Google Scholar 

  • Bae DS, Cho SB, Kim YJ, Whang JD, Song SY, Park CS et al. (2001). Aberrant expression of cyclin D1 is associated with poor prognosis in early stage cervical cancer of the uterus. Gynecol Oncol 81: 341–347.

    Article  CAS  PubMed  Google Scholar 

  • Belsham GJ, Sonenberg N, Svitkin YV . (1995). The role of the La autoantigen in internal initiation. Curr Top Microbiol Immunol 203: 85–98.

    CAS  PubMed  Google Scholar 

  • Brenet F, Dussault N, Borch J, Ferracci G, Delfino C, Roepstorff P et al. (2005). Mammalian peptidylglycine alpha-amidating monooxygenase mRNA expression can be modulated by the La autoantigen. Mol Cell Biol 25: 7505–7521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brenet F, Socci ND, Sonenberg N, Holland EC . (2009). Akt phosphorylation of La regulates specific mRNA translation in glial progenitors. Oncogene 28: 128–139.

    Article  CAS  PubMed  Google Scholar 

  • Calkhoven CF, Muller C, Leutz A . (2000). Translational control of C/EBPalpha and C/EBPbeta isoform expression. Genes Dev 14: 1920–1932.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Carreras R, Alameda F, Mancebo G, Garcia-Moreno P, Marinoso ML, Costa C et al. (2007). A study of Ki-67, c-erbB2 and cyclin D-1 expression in CIN-I, CIN-III and squamous cell carcinoma of the cervix. Histol Histopathol 22: 587–592.

    CAS  PubMed  Google Scholar 

  • Chang YN, Kenan DJ, Keene JD, Gatignol A, Jeang KT . (1995). Direct interactions between autoantigen la and human immunodeficiency virus leader RNA. J Virol 69: 618–619.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chellappan S, Kraus VB, Kroger B, Munger K, Howley PM, Phelps WC et al. (1992). Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product. Proc Natl Acad Sci USA 89: 4549–4553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheung TH, Yu MM, Lo KW, Yim SF, Chung TK, Wong YF . (2001). Alteration of cyclin D1 and CDK4 gene in carcinoma of uterine cervix. Cancer Lett 166: 199–206.

    Article  CAS  PubMed  Google Scholar 

  • Conesa-Zamora P, Domenech-Peris A, Orantes-Casado FJ, Ortiz-Reina S, Sahuquillo-Frias L, Acosta-Ortega J et al. (2009). Effect of human papillomavirus on cell cycle-related proteins p16, Ki-67, Cyclin D1, p53, and ProEx C in precursor lesions of cervical carcinoma: a tissue microarray study. Am J Clin Pathol 132: 378–390.

    Article  PubMed  Google Scholar 

  • Cordes S, Kusov Y, Heise T, Gauss-Muller V . (2008). La autoantigen suppresses IRES-dependent translation of the hepatitis A virus. Biochem Biophys Res Commun 368: 1014–1019.

    Article  CAS  PubMed  Google Scholar 

  • Costa-Mattioli M, Svitkin Y, Sonenberg N . (2004). La autoantigen is necessary for optimal function of the poliovirus and hepatitis C virus internal ribosome entry site in vivo and in vitro. Mol Cell Biol 24: 6861–6870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cowling VH . (2010). Enhanced mRNA cap methylation increases cyclin D1 expression and promotes cell transformation. Oncogene 29: 930–936.

    Article  CAS  PubMed  Google Scholar 

  • Crosio C, Boyl PP, Loreni F, Pierandrei-Amaldi P, Amaldi F . (2000). La protein has a positive effect on the translation of top mRNAs in vivo. Nucl Acids Res 28: 2927–2934.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diehl JA . (2002). Cycling to cancer with cyclin D1. Cancer Biol Ther 1: 226–231.

    Article  CAS  PubMed  Google Scholar 

  • Ehlers I, Horke S, Reumann K, Rang A, Grosse F, Will H et al. (2004). Functional characterization of the interaction between human La and hepatitis B virus RNA. J Biol Chem 279: 43437–43447. Epub 2004 Aug 9.

    Article  CAS  PubMed  Google Scholar 

  • Frost P, Shi Y, Hoang B, Gera J, Lichtenstein A . (2009). Regulation of D-cyclin translation inhibition in myeloma cells treated with mammalian target of rapamycin inhibitors: rationale for combined treatment with extracellular signal-regulated kinase inhibitors and rapamycin. Mol Cancer Ther 8: 83–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fu M, Wang C, Li Z, Sakamaki T, Pestell RG . (2004). Minireview: Cyclin D1: normal and abnormal functions. Endocrinology 145: 5439–5447.

    Article  CAS  PubMed  Google Scholar 

  • Holcik M, Korneluk RG . (2000). Functional characterization of the X-linked inhibitor of apoptosis (XIAP) internal ribosome entry site element: role of La autoantigen in XIAP translation. Mol Cell Biol 20: 4648–4657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horke S, Reumann K, Schweizer M, Will H, Heise T . (2004). Nuclear trafficking of La protein depends on a newly identified nucleolar localization signal and the ability to bind RNA. J Biol Chem 279: 26563–26570.

    Article  CAS  PubMed  Google Scholar 

  • Inge LJ, Rajasekaran SA, Wolle D, Barwe SP, Ryazantsev S, Ewing CM et al. (2008). alpha-Catenin overrides Src-dependent activation of beta-catenin oncogenic signaling. Mol Cancer Ther 7: 1386–1397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jo OD, Martin J, Bernath A, Masri J, Lichtenstein A, Gera J . (2008). Heterogeneous nuclear ribonucleoprotein A1 regulates cyclin D1 and c-myc internal ribosome entry site function through Akt signaling. J Biol Chem 283: 23274–23287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim YK, Back SH, Rho J, Lee SH, Jang SK . (2001). La autoantigen enhances translation of BiP mRNA. Nucleic Acids Res 29: 5009–5016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Knudsen KE, Diehl JA, Haiman CA, Knudsen ES . (2006). Cyclin D1: polymorphism, aberrant splicing and cancer risk. Oncogene 25: 1620–1628.

    Article  CAS  PubMed  Google Scholar 

  • Lamb J, Ramaswamy S, Ford HL, Contreras B, Martinez RV, Kittrell FS et al. (2003). A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer. Cell 114: 323–334.

    Article  CAS  PubMed  Google Scholar 

  • Maraia RJ . (2001). La protein and the trafficking of nascent RNA polymerase iii transcripts. J Cell Biol 153: F13–F18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maraia RJ, Intine RV . (2002). La protein and its associated small nuclear and nucleolar precursor RNAs. Gene Expr 10: 41–57.

    CAS  PubMed  Google Scholar 

  • McLaren R, Caruccio N, Ross J . (1997). Human La protein: a stabilizer of histone mRNA. Mol Cell Biol 17: 3028–3036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McLaughlin-Drubin ME, Munger K . (2009). The human papillomavirus E7 oncoprotein. Virology 384: 335–344.

    Article  CAS  PubMed  Google Scholar 

  • Motokura T, Bloom T, Kim HG, Juppner H, Ruderman JV, Kronenberg HM et al. (1991). A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature 350: 512–515.

    Article  CAS  PubMed  Google Scholar 

  • Muise-Helmericks RC, Grimes HL, Bellacosa A, Malstrom SE, Tsichlis PN, Rosen N . (1998). Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem 273: 29864–29872.

    Article  CAS  PubMed  Google Scholar 

  • Musgrove EA . (2006). Cyclins: roles in mitogenic signaling and oncogenic transformation. Growth Factors 24: 13–19.

    Article  CAS  PubMed  Google Scholar 

  • Nerlov C . (2007). The C/EBP family of transcription factors: a paradigm for interaction between gene expression and proliferation control. Trends Cell Biol 17: 318–324.

    Article  CAS  PubMed  Google Scholar 

  • Nichols GE, Williams ME, Gaffey MJ, Stoler MH . (1996). Cyclin D1 gene expression in human cervical neoplasia. Mod Pathol 9: 418–425.

    CAS  PubMed  Google Scholar 

  • Niranjanakumari S, Lasda E, Brazas R, Garcia-Blanco MA . (2002). Reversible cross-linking combined with immunoprecipitation to study RNA-protein interactions in vivo. Methods 26: 182–190.

    Article  CAS  PubMed  Google Scholar 

  • Park JM, Kohn MJ, Bruinsma MW, Vech C, Intine RV, Fuhrmann S et al. (2006). The multifunctional RNA-binding protein La is required for mouse development and for the establishment of embryonic stem cells. Mol Cell Biol 26: 1445–1451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pudi R, Srinivasan P, Das S . (2004). La protein binding at the GCAC site near the initiator AUG facilitates the ribosomal assembly on the hepatitis C virus RNA to influence internal ribosome entry site-mediated translation. J Biol Chem 279: 29879–29888.

    Article  CAS  PubMed  Google Scholar 

  • Sebastian T, Malik R, Thomas S, Sage J, Johnson PF . (2005). C/EBPbeta cooperates with RB:E2F to implement Ras(V12)-induced cellular senescence. Embo J 24: 3301–3312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi Y, Sharma A, Wu H, Lichtenstein A, Gera J . (2005). Cyclin D1 and c-myc internal ribosome entry site (IRES)-dependent translation is regulated by AKT activity and enhanced by rapamycin through a p38 MAPK- and ERK-dependent pathway. J Biol Chem 280: 10964–10973.

    Article  CAS  PubMed  Google Scholar 

  • Spangberg K, Wiklund L, Schwartz S . (2001). Binding of the La autoantigen to the hepatitis C virus 3′ untranslated region protects the RNA from rapid degradation in vitro. J Gen Virol 82: 113–120.

    Article  CAS  PubMed  Google Scholar 

  • Svitkin YV, Pause A, Sonenberg N . (1994). La autoantigen alleviates translational repression by the 5′ leader sequence of the human immunodeficiency virus type 1 mRNA. J Virol 68: 7001–7007.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Trotta R, Vignudelli T, Candini O, Intine RV, Pecorari L, Guerzoni C et al. (2003). BCR/ABL activates mdm2 mRNA translation via the La antigen. Cancer Cell 3: 145–160.

    Article  CAS  PubMed  Google Scholar 

  • Wang C, Pattabiraman N, Zhou JN, Fu M, Sakamaki T, Albanese C et al. (2003). Cyclin D1 repression of peroxisome proliferator-activated receptor gamma expression and transactivation. Mol Cell Biol 23: 6159–6173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolin SL, Cedervall T . (2002). The La protein. Annu Rev Biochem 71: 375–403.

    Article  CAS  PubMed  Google Scholar 

  • Zahnow CA . (2009). CCAAT/enhancer-binding protein beta: its role in breast cancer and associations with receptor tyrosine kinases. Expert Rev Mol Med 11: e12.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Arne Düsedau (HPI) for sorting GFP-positive cells and Rick Peppler for FACS analysis (MUSC). We are grateful to R G Pestell (Thomas Jefferson University) for providing the MEFCCND1−/− cells, to M Bachmann (Technical University Dresden, Germany) for providing La antibodies, to Josef Gera for providing the CCND1-IRES reporter plasmid pRCD1F, to D Watson (MUSC) for experimental advice during this study, and D Fernandes (MUSC) and J Schnellmann (MUSC) for critical reading of the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft, HE 2814/3-2 (TH). The Heinrich-Pette-Institut (HPI) is financially supported by the Bundesministerium für Gesundheit and Freie und Hansestadt Hamburg.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA

    G Sommer, J Dittmann, J Kuehnert & T Heise

  2. Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie, Hamburg, Germany

    J Dittmann, K Reumann, H Will & T Heise

  3. Protein Biotechnologies, Inc., Ramona, CA, USA

    P E Schwartz

  4. Department of Pathology & Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA

    B L Coulter & M T Smith

Authors
  1. G Sommer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Dittmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Kuehnert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Reumann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P E Schwartz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Will
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B L Coulter
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M T Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. T Heise
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Heise.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website ()

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sommer, G., Dittmann, J., Kuehnert, J. et al. The RNA-binding protein La contributes to cell proliferation and CCND1 expression. Oncogene 30, 434–444 (2011). https://doi.org/10.1038/onc.2010.425

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.425

Keywords

This article is cited by

Search

Advanced search

Quick links