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PARP14 regulates cyclin D1 expression to promote cell-cycle progression

Oncogene volume 40, pages 4872–4883 (2021)Cite this article

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Abstract

Cyclin D1 is an essential regulator of the G1–S cell-cycle transition and is overexpressed in many cancers. Expression of cyclin D1 is under tight cellular regulation that is controlled by many signaling pathways. Here we report that PARP14, a member of the poly(ADP-ribose) polymerase (PARP) family, is a regulator of cyclin D1 expression. Depletion of PARP14 leads to decreased cyclin D1 protein levels. In cells with a functional retinoblastoma (RB) protein pathway, this results in G1 cell-cycle arrest and reduced proliferation. Mechanistically, we found that PARP14 controls cyclin D1 mRNA levels. Using luciferase assays, we show that PARP14 specifically regulates cyclin D1 3′UTR mRNA stability. Finally, we also provide evidence that G1 arrest in PARP14-depleted cells is dependent on an intact p53–p21 pathway. Our work uncovers a new role for PARP14 in promoting cell-cycle progression through both cyclin D1 and the p53 pathway.

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Fig. 1: PARP14 is required for cell-cycle progression.
Fig. 2: PARP14 is required for RB phosphorylation and E2F1 target protein expression.
Fig. 3: Cell-cycle arrest due to PARP14 knockdown is not observed in RPE-1 RB/p107/p130 triple knockout cells or HeLa cells.
Fig. 4: Depletion of p21 or p53 moderately rescues cell-cycle arrest caused by PARP14 knockdown.
Fig. 5: PARP14 regulates Cyclin D1 protein expression and mRNA levels.
Fig. 6: Overexpression of Cyclin D1 rescues both the E2F1 protein expression and the CDK4/6 kinase activity defects caused by PARP14 knockdown.
Fig. 7: PARP14 is required for Cyclin D1 3′UTR mRNA stability.

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Data availability

All source data underlying each figure, including the values plotted in graphs, the exact p values, and the uncropped blots are presented in Supplementary Table S1.

References

  1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  2. Narasimha AM, Kaulich M, Shapiro GS, Choi YJ, Sicinski P, Dowdy SF. Cyclin D activates the Rb tumor suppressor by mono-phosphorylation. Elife. 2014;3:e02872

    Article  PubMed Central  CAS  Google Scholar 

  3. Wells J, Graveel CR, Bartley SM, Madore SJ, Farnham PJ. The identification of E2F1-specific target genes. Proc Natl Acad Sci U S A. 2002;99:3890–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Velez-Cruz R, Johnson DG. The retinoblastoma (RB) tumor suppressor: pushing back against genome instability on multiple fronts. Int J Mol Sci. 2017;18:1776

    Article  PubMed Central  CAS  Google Scholar 

  5. Viatour P, Sage J. Newly identified aspects of tumor suppression by RB. Dis Model Mech. 2011;4:581–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ertel A, Dean JL, Rui H, Liu C, Witkiewicz AK, Knudsen KE, et al. RB-pathway disruption in breast cancer: differential association with disease subtypes, disease-specific prognosis and therapeutic response. Cell Cycle. 2010;9:4153–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375:1925–36.

    Article  CAS  PubMed  Google Scholar 

  8. Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35:3638–46.

    Article  CAS  PubMed  Google Scholar 

  9. Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381:307–16.

    Article  CAS  PubMed  Google Scholar 

  10. Dyson NJ. RB1: a prototype tumor suppressor and an enigma. Genes Dev. 2016;30:1492–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Klein EA, Assoian RK. Transcriptional regulation of the cyclin D1 gene at a glance. J Cell Sci. 2008;121:3853–7.

    Article  CAS  PubMed  Google Scholar 

  12. Harper JW, Elledge SJ, Keyomarsi K, Dynlacht B, Tsai LH, Zhang P, et al. Inhibition of cyclin-dependent kinases by p21. Mol Biol Cell. 1995;6:387–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, et al. New functional activities for the p21 family of CDK inhibitors. Genes Dev. 1997;11:847–62.

    Article  CAS  PubMed  Google Scholar 

  14. Vyas S, Matic I, Uchima L, Rood J, Zaja R, Hay RT, et al. Family-wide analysis of poly(ADP-ribose) polymerase activity. Nat Commun. 2014;5:4426.

    Article  CAS  PubMed  Google Scholar 

  15. Carbone M, Rossi MN, Cavaldesi M, Notari A, Amati P, Maione R. Poly(ADP-ribosyl)ation is implicated in the G0-G1 transition of resting cells. Oncogene. 2008;27:6083–92.

    Article  CAS  PubMed  Google Scholar 

  16. Augustin A, Spenlehauer C, Dumond H, Menissier-De Murcia J, Piel M, Schmit AC, et al. PARP-3 localizes preferentially to the daughter centriole and interferes with the G1/S cell cycle progression. J Cell Sci. 2003;116:1551–62.

    Article  CAS  PubMed  Google Scholar 

  17. Nicolae CM, Aho ER, Choe KN, Constantin D, Hu HJ, Lee D, et al. A novel role for the mono-ADP-ribosyltransferase PARP14/ARTD8 in promoting homologous recombination and protecting against replication stress. Nucleic Acids Res. 2015;43:3143–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Goenka S, Boothby M. Selective potentiation of Stat-dependent gene expression by collaborator of Stat6 (CoaSt6), a transcriptional cofactor. Proc Natl Acad Sci U S A. 2006;103:4210–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vyas S, Chesarone-Cataldo M, Todorova T, Huang YH, Chang P. A systematic analysis of the PARP protein family identifies new functions critical for cell physiology. Nat Commun. 2013;4:2240.

    Article  PubMed  CAS  Google Scholar 

  20. Cho SH, Goenka S, Henttinen T, Gudapati P, Reinikainen A, Eischen CM, et al. PARP-14, a member of the B aggressive lymphoma family, transduces survival signals in primary B cells. Blood. 2009;113:2416–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Barbarulo A, Iansante V, Chaidos A, Naresh K, Rahemtulla A, Franzoso G, et al. Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma. Oncogene. 2013;32:4231–42.

    Article  CAS  PubMed  Google Scholar 

  22. Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11:R77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Lee MS, Helms TL, Feng N, Gay J, Chang QE, Tian F, et al. Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models. Oncotarget. 2016;7:39595–608.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sherr CJ, Beach D, Shapiro GI. Targeting CDK4 and CDK6: from discovery to therapy. Cancer Discov. 2016;6:353–67.

    Article  CAS  PubMed  Google Scholar 

  25. Nicolay BN, Danielian PS, Kottakis F, Lapek JD Jr., Sanidas I, Miles WO, et al. Proteomic analysis of pRb loss highlights a signature of decreased mitochondrial oxidative phosphorylation. Genes Dev. 2015;29:1875–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kettner NM, Vijayaraghavan S, Durak MG, Bui T, Kohansal M, Ha MJ, et al. Combined inhibition of STAT3 and DNA repair in palbociclib-resistant ER-positive breast cancer. Clin Cancer Res. 2019;25:3996–4013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Stengel KR, Thangavel C, Solomon DA, Angus SP, Zheng Y, Knudsen ES. Retinoblastoma/p107/p130 pocket proteins: protein dynamics and interactions with target gene promoters. J Biol Chem. 2009;284:19265–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Farkas T, Hansen K, Holm K, Lukas J, Bartek J. Distinct phosphorylation events regulate p130- and p107-mediated repression of E2F-4. J Biol Chem. 2002;277:26741–52.

    Article  CAS  PubMed  Google Scholar 

  29. Benedict B, van Harn T, Dekker M, Hermsen S, Kucukosmanoglu A, Pieters W. et al. Loss of p53 suppresses replication-stress-induced DNA breakage in G1/S checkpoint deficient cells. Elife. 2018;7:e37868.

    Article  PubMed  PubMed Central  Google Scholar 

  30. DeFilippis RA, Goodwin EC, Wu L, DiMaio D. Endogenous human papillomavirus E6 and E7 proteins differentially regulate proliferation, senescence, and apoptosis in HeLa cervical carcinoma cells. J Virol. 2003;77:1551–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. He G, Siddik ZH, Huang Z, Wang R, Koomen J, Kobayashi R, et al. Induction of p21 by p53 following DNA damage inhibits both Cdk4 and Cdk2 activities. Oncogene. 2005;24:2929–43.

    Article  CAS  PubMed  Google Scholar 

  32. Yang Z, Maciejowski J, de Lange T. Nuclear envelope rupture is enhanced by loss of p53 or Rb. Mol Cancer Res. 2017;15:1579–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP, et al. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science. 1998;282:1497–501.

    Article  CAS  PubMed  Google Scholar 

  34. Guiley KZ, Stevenson JW, Lou K, Barkovich KJ, Kumarasamy V, Wijeratne TU. et al. p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition. Science. 2019;366:eaaw2106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Muise-Helmericks RC, Grimes HL, Bellacosa A, Malstrom SE, Tsichlis PN, Rosen N. Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem. 1998;273:29864–72.

    Article  CAS  PubMed  Google Scholar 

  36. Chambard JC, Lefloch R, Pouyssegur J, Lenormand P. ERK implication in cell cycle regulation. Biochim Biophys Acta. 2007;1773:1299–310.

    Article  CAS  PubMed  Google Scholar 

  37. Zhang J, Xu K, Liu P, Geng Y, Wang B, Gan W, et al. Inhibition of Rb phosphorylation leads to mTORC2-mediated activation of Akt. Mol Cell. 2016;62:929–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999;398:422–6.

    Article  CAS  PubMed  Google Scholar 

  39. Hydbring P, Wang Y, Fassl A, Li X, Matia V, Otto T, et al. Cell-cycle-targeting MicroRNAs as therapeutic tools against refractory cancers. Cancer Cell. 2017;31:576–90.e8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Iqbal MB, Johns M, Cao J, Liu Y, Yu SC, Hyde GD, et al. PARP-14 combines with tristetraprolin in the selective posttranscriptional control of macrophage tissue factor expression. Blood. 2014;124:3646–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Milek M, Imami K, Mukherjee N, Bortoli F, Zinnall U, Hazapis O, et al. DDX54 regulates transcriptome dynamics during DNA damage response. Genome Res. 2017;27:1344–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Riley JP, Kulkarni A, Mehrotra P, Koh B, Perumal NB, Kaplan MH, et al. PARP-14 binds specific DNA sequences to promote Th2 cell gene expression. PLoS ONE. 2013;8:e83127.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Mayr C. Regulation by 3’-untranslated regions. Annu Rev Genet. 2017;51:171–94.

    Article  CAS  PubMed  Google Scholar 

  44. Yao N, Chen Q, Shi W, Tang L, Fu Y. PARP14 promotes the proliferation and gemcitabine chemoresistance of pancreatic cancer cells through activation of NF-kappaB pathway. Mol Carcinog. 2019;58:1291–302.

    CAS  PubMed  Google Scholar 

  45. Iansante V, Choy PM, Fung SW, Liu Y, Chai JG, Dyson J, et al. PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation. Nat Commun. 2015;6:7882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nicolae CM, Aho ER, Vlahos AH, Choe KN, De S, Karras GI, et al. The ADP-ribosyltransferase PARP10/ARTD10 interacts with proliferating cell nuclear antigen (PCNA) and is required for DNA damage tolerance. J Biol Chem. 2014;289:13627–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nicolae CM, O’Connor MJ, Constantin D, Moldovan GL. NFkappaB regulates p21 expression and controls DNA damage-induced leukemic differentiation. Oncogene. 2018;37:3647–56.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Drs James Broach, Gregory Yochum, Lisa Shantz, Hein Te Riele, Titia de Lange, Nicholas Dyson, Hong-Gang Wang, Raymond Hohl, Myriam Gorospe, Khandan Keyomarsi, and Peter Sicinski for materials and advice, as well as the Penn State College of Medicine Flow Cytometry core for their assistance with flow cytometry experiments. This work was supported by NIH R01ES026184 (to G-LM).

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  1. Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA

    Michael J. O’Connor, Tanay Thakar, Claudia M. Nicolae & George-Lucian Moldovan

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Correspondence to George-Lucian Moldovan.

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O’Connor, M.J., Thakar, T., Nicolae, C.M. et al. PARP14 regulates cyclin D1 expression to promote cell-cycle progression. Oncogene 40, 4872–4883 (2021). https://doi.org/10.1038/s41388-021-01881-8

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