p19INK4d: More than Just a Cyclin-Dependent Kinase Inhibitor

Author(s): Xu Han, Yijin Kuang, Huiyong Chen, Ting Liu, Ji Zhang*, Jing Liu*.

Journal Name: Current Drug Targets

Volume 21 , Issue 1 , 2020

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Abstract:

Cyclin-dependent kinase inhibitors (CDKIs) are important cell cycle regulators. The CDKI family is composed of the INK4 family and the CIP/KIP family. p19INK4d belongs to the INK4 gene family and is involved in a series of normal physiological activities and the pathogenesis of diseases. Many factors play regulatory roles in the p19INK4d gene expression at the transcriptional and posttranscriptional levels. p19INK4d not only regulates the cell cycle but also plays regulatory roles in apoptosis, DNA damage repair, cell differentiation of hematopoietic cells, and cellular senescence. In this review, the regulatory network of the p19INK4d gene expression and its biological functions are summarized, which provides a basis for further study of p19INK4d as a drug target for disease treatment.

Keywords: CDKI, p19INK4d, expression regulation, biological function, INK4, CIP/KIP.

[1]
Matson JP, Cook JG. Cell cycle proliferation decisions: the impact of single cell analyses. FEBS J 2017; 284(3): 362-75.
[http://dx.doi.org/10.1111/febs.13898] [PMID: 27634578]
[2]
Dalton S. Linking the cell cycle to cell fate decisions. Trends Cell Biol 2015; 25(10): 592-600.
[http://dx.doi.org/10.1016/j.tcb.2015.07.007] [PMID: 26410405]
[3]
Soufi A, Dalton S. Cycling through developmental decisions: how cell cycle dynamics control pluripotency, differentiation and reprogramming. Development 2016; 143(23): 4301-11.
[http://dx.doi.org/10.1242/dev.142075] [PMID: 27899507]
[4]
Childs BG, Gluscevic M, Baker DJ, et al. Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov 2017; 16(10): 718-35.
[http://dx.doi.org/10.1038/nrd.2017.116] [PMID: 28729727]
[5]
Abbastabar M, Kheyrollah M, Azizian K, et al. Multiple functions of p27 in cell cycle, apoptosis, epigenetic modification and transcriptional regulation for the control of cell growth: A double-edged sword protein. DNA Repair (Amst) 2018; 69: 63-72.
[http://dx.doi.org/10.1016/j.dnarep.2018.07.008] [PMID: 30075372]
[6]
Lim S, Kaldis P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development 2013; 140(15): 3079-93.
[http://dx.doi.org/10.1242/dev.091744] [PMID: 23861057]
[7]
Truman AW, Kitazono AA, Fitz Gerald JN, et al. Cell Cycle: Regulation by Cyclins 2012.
[8]
Arellano M, Moreno S. Regulation of CDK/cyclin complexes during the cell cycle. Int J Biochem Cell Biol 1997; 29(4): 559-73.
[http://dx.doi.org/10.1016/S1357-2725(96)00178-1] [PMID: 9363633]
[9]
Chiu HC, Huang WR, Liao TL, et al. Mechanistic insights into avian reovirus p17-modulated suppression of cell cycle CDK-cyclin complexes and enhancement of p53 and cyclin H interaction. J Biol Chem 2018; 293(32): 12542-62.
[http://dx.doi.org/10.1074/jbc.RA118.002341] [PMID: 29907572]
[10]
Besson A, Dowdy SF, Roberts JM. CDK inhibitors: cell cycle regulators and beyond. Dev Cell 2008; 14(2): 159-69.
[http://dx.doi.org/10.1016/j.devcel.2008.01.013] [PMID: 18267085]
[11]
Cheng T. Cell cycle inhibitors in normal and tumor stem cells. Oncogene 2004; 23(43): 7256-66.
[http://dx.doi.org/10.1038/sj.onc.1207945] [PMID: 15378085]
[12]
Roskoski R Jr. Cyclin-dependent protein serine/threonine kinase inhibitors as anticancer drugs 2019; 139: 471-88.
[13]
Buchkovich K, Duffy LA, Harlow E. The retinoblastoma protein is phosphorylated during specific phases of the cell cycle. Cell 1989; 58(6): 1097-105.
[http://dx.doi.org/10.1016/0092-8674(89)90508-4] [PMID: 2673543]
[14]
Grinstein E, Shan Y, Karawajew L, et al. Cell cycle-controlled interaction of nucleolin with the retinoblastoma protein and cancerous cell transformation. J Biol Chem 2006; 281(31): 22223-35.
[http://dx.doi.org/10.1074/jbc.M513335200] [PMID: 16698799]
[15]
Kent LN, Leone G. The retinoblastoma protein is phosphorylated during specific phases of the cell cycle. Cell 2019; 58(6): 1097-5.
[16]
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: 3.
[http://dx.doi.org/10.7554/eLife.02872] [PMID: 24876129]
[17]
Okuda T, Hirai H, Valentine VA, et al. Molecular cloning, expression pattern, and chromosomal localization of human CDKN2D/INK4d, an inhibitor of cyclin D-dependent kinases. Genomics 1995; 29(3): 623-30.
[http://dx.doi.org/10.1006/geno.1995.9957] [PMID: 8575754]
[18]
Doherty JR, Nilsson LM, Kuliyev E, et al. Embryonic Expression and Function of the Xenopus Ink4d Cyclin D-Dependent Kinase Inhibitor 2014; 3(1): 133.
[19]
Kalus W, Baumgartner R, Renner C, et al. NMR structural characterization of the CDK inhibitor p19INK4d. FEBS Lett 1997; 401(2-3): 127-32.
[http://dx.doi.org/10.1016/S0014-5793(96)01465-2] [PMID: 9013872]
[20]
Han J, Ito Y, Yeo JY, Sucov HM, Maas R, Chai Y. Cranial neural crest-derived mesenchymal proliferation is regulated by Msx1-mediated p19(INK4d) expression during odontogenesis. Dev Biol 2003; 261(1): 183-96.
[http://dx.doi.org/10.1016/S0012-1606(03)00300-2] [PMID: 12941628]
[21]
Zhao M, Gupta V, Raj L, Roussel M, Bei M. A network of transcription factors operates during early tooth morphogenesis. Mol Cell Biol 2013; 33(16): 3099-112.
[http://dx.doi.org/10.1128/MCB.00524-13] [PMID: 23754753]
[22]
Gilles L, Guièze R, Bluteau D, et al. P19INK4D links endomitotic arrest and megakaryocyte maturation and is regulated by AML-1. Blood 2008; 111(8): 4081-91.
[http://dx.doi.org/10.1182/blood-2007-09-113266] [PMID: 18276842]
[23]
Rice KL, Hormaeche I, Doulatov S, et al. Comprehensive genomic screens identify a role for PLZF-RARalpha as a positive regulator of cell proliferation via direct regulation of c-MYC. Blood 2009; 114(27): 5499-511.
[http://dx.doi.org/10.1182/blood-2009-03-206524] [PMID: 19855079]
[24]
Wang Y, Jin W, Jia X, et al. Transcriptional repression of CDKN2D by PML/RARα contributes to the altered proliferation and differentiation block of acute promyelocytic leukemia cells. Cell Death Dis 2014.5e1431
[http://dx.doi.org/10.1038/cddis.2014.388] [PMID: 25275592]
[25]
Carcagno AL, Giono LE, Marazita MC, Castillo DS, Pregi N, Cánepa ET. E2F1 induces p19INK4d, a protein involved in the DNA damage response, following UV irradiation. Mol Cell Biochem 2012; 366(1-2): 123-9.
[http://dx.doi.org/10.1007/s11010-012-1289-8] [PMID: 22476863]
[26]
Katayama K, Nakamura A, Sugimoto Y, Tsuruo T, Fujita N. FOXO transcription factor-dependent p15(INK4b) and p19(INK4d) expression. Oncogene 2008; 27(12): 1677-86.
[http://dx.doi.org/10.1038/sj.onc.1210813] [PMID: 17873901]
[27]
Liu YY, Zhang YN, Yang QS. Downregulated expression of microRNA-329 inhibits apoptosis of nigral dopaminergic neurons by regulating CDKN2D expression via the FoxO3a signaling pathway in rats with Parkinson’s disease. J Cell Physiol 2018; 233(11): 8617-29.
[http://dx.doi.org/10.1002/jcp.26608] [PMID: 29761857]
[28]
Song KH, Choi CH, Lee HJ, et al. HDAC1 Upregulation by NANOG promotes multidrug resistance and a stem-like phenotype in immune edited tumor cells. Cancer Res 2017; 77(18): 5039-3.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-0072]
[29]
Yokota T, Matsuzaki Y, Miyazawa K, Zindy F, Roussel MF, Sakai T. Histone deacetylase inhibitors activate INK4d gene through Sp1 site in its promoter. Oncogene 2004; 23(31): 5340-9.
[http://dx.doi.org/10.1038/sj.onc.1207689] [PMID: 15107822]
[30]
Zhou H, Cai Y, Liu D, et al. Pharmacological or transcriptional inhibition of both HDAC1 and 2 leads to cell cycle blockage and apoptosis via p21Waf1/Cip1 and p19INK4d upregulation in hepatocellular carcinoma. Cell Prolif 2018; 51(3)e12447
[http://dx.doi.org/10.1111/cpr.12447] [PMID: 29484736]
[31]
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116(2): 281-97.
[http://dx.doi.org/10.1016/S0092-8674(04)00045-5] [PMID: 14744438]
[32]
Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases 2017; 16(3): 203-.
[http://dx.doi.org/10.1038/nrd.2016.246]
[33]
Zhang J, Xiao X, Liu J. The role of circulating miRNAs in multiple myeloma 2015; 58(12): 1262-9.
[http://dx.doi.org/10.1007/s11427-015-4969-2]
[34]
Zhang J, Jiang Y, Han X, et al. Differential expression profiles and functional analysis of plasma miRNAs associated with chronic myeloid leukemia phases. Future Oncol 2019; 15(7): 763-76.
[http://dx.doi.org/10.2217/fon-2018-0741]
[35]
Catalanotto C, Cogoni C, Zardo G. MicroRNA in control of gene expression: an overview of nuclear functions. Int J Mol Sci 2016; 17(10)E1712
[http://dx.doi.org/10.3390/ijms17101712] [PMID: 27754357]
[36]
Zang WQ, Yang X, Wang T, et al. MiR-451 inhibits proliferation of esophageal carcinoma cell line EC9706 by targeting CDKN2D and MAP3K1. World J Gastroenterol 2015; 21(19): 5867-76.
[http://dx.doi.org/10.3748/wjg.v21.i19.5867] [PMID: 26019450]
[37]
Trattnig C, Üçal M, Tam-Amersdorfer C, et al. MicroRNA-451a overexpression induces accelerated neuronal differentiation of Ntera2/D1 cells and ablation affects neurogenesis in microRNA-451a-/- mice. PLoS One 2018; 13(11)e0207575
[http://dx.doi.org/10.1371/journal.pone.0207575] [PMID: 30462722]
[38]
Qu M, Fang F, Zou X, et al. miR-125b modulates megakaryocyte maturation by targeting the cell-cycle inhibitor p19INK4D. Cell Death Dis 2016; 7(10)e2430
[http://dx.doi.org/10.1038/cddis.2016.288] [PMID: 27763644]
[39]
Kołodziejczak M, Opalińska M, Czarna M, Jańska H. [ATPdependent proteases in the quality control of mitochondrial proteome] Postepy Biochem 2016; 62(2): 206-15.
[PMID: 28132473]
[40]
Smakowska E, Czarna M, Janska H. Mitochondrion JHJ. Mitochondrial ATP-dependent proteases in protection against accumulation of carbonylated proteins. Mitochondrion 2014; 245-51.
[41]
Joy J, Nalabothula N, Ghosh M, et al. Identification of calpain cleavage sites in the G1 cyclin-dependent kinase inhibitor p19(INK4d). Biol Chem 2006; 387(3): 329-35.
[http://dx.doi.org/10.1515/BC.2006.044] [PMID: 16542156]
[42]
Kumar A, Gopalswamy M, Wolf A, Brockwell DJ, Hatzfeld M, Balbach J. Phosphorylation-induced unfolding regulates p19INK4d during the human cell cycle. Proc Natl Acad Sci USA 2018; 115(13): 3344-9.
[http://dx.doi.org/10.1073/pnas.1719774115] [PMID: 29531090]
[43]
Forget A, Ayrault O, den Besten W, Kuo ML, Sherr CJ, Roussel MF. Differential post-transcriptional regulation of two Ink4 proteins, p18 Ink4c and p19 Ink4d. Cell Cycle 2008; 7(23): 3737-46.
[http://dx.doi.org/10.4161/cc.7.23.7187] [PMID: 19029828]
[44]
Dreidax D, Bannert S, Henrich KO, et al. p19-INK4d inhibits neuroblastoma cell growth, induces differentiation and is hypermethylated and downregulated in MYCN-amplified neuroblastomas. Hum Mol Genet 2014; 23(25): 6826-37.
[http://dx.doi.org/10.1093/hmg/ddu406] [PMID: 25104850]
[45]
Lin S, Wang MJ, Tseng KY. Polypyrimidine tract-binding protein induces p19(Ink4d) expression and inhibits the proliferation of H1299 cells. PLoS One 2013; 8(3)e58227
[http://dx.doi.org/10.1371/journal.pone.0058227] [PMID: 23536791]
[46]
Zhong L, Liao G, Wang X, et al. Mesenchymal stem cellsmicrovesicle- miR-451a ameliorate early diabetic kidney injury by negative regulation of P15 and P19. Exp Biol Med 2019.1535370218819726
[PMID: 30614256]
[47]
O’Farrell AM, Parry DA, Zindy F, et al. Stat3-dependent induction of p19INK4D by IL-10 contributes to inhibition of macrophage proliferation. J Immunol 2000; 164(9): 4607-15.
[48]
Narimatsu M, Nakajima K, Ichiba M, Hirano T. Association of Stat3-dependent transcriptional activation of p19INK4D with IL-6-induced growth arrest. Biochem Biophys Res Commun 1997; 238(3): 764-8.
[http://dx.doi.org/10.1006/bbrc.1997.7387] [PMID: 9325164]
[49]
Matsuoka M, Tani K, Asano S. Interferon-alpha-induced G1 phase arrest through up-regulated expression of CDK inhibitors, p19Ink4D and p21Cip1 in mouse macrophages. Oncogene 1998; 16(16): 2075-86.
[http://dx.doi.org/10.1038/sj.onc.1201745] [PMID: 9572488]
[50]
Rao SS, O’Neil J, Liberator CD, et al. Inhibition of NOTCH signaling by gamma secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells. Cancer Res 2009; 69(7): 3060-8.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-4295] [PMID: 19318552]
[51]
Bai F, Chan HL, Smith MD, Kiyokawa H, Pei XH. p19Ink4d is a tumor suppressor and controls pituitary anterior lobe cell proliferation. Mol Cell Biol 2014; 34(12): 2121-34.
[http://dx.doi.org/10.1128/MCB.01363-13] [PMID: 24687853]
[52]
Miller CW, Yeon C, Aslo A, Mendoza S, Aytac U, Koeffler HP. The p19INK4D cyclin dependent kinase inhibitor gene is altered in osteosarcoma. Oncogene 1997; 15(2): 231-5.
[http://dx.doi.org/10.1038/sj.onc.1201185] [PMID: 9244358]
[53]
Marazita MC, Ogara MF, Sonzogni SV, et al. CDK2 and PKA mediated-sequential phosphorylation is critical for p19INK4d function in the DNA damage response. PLoS One 2012; 7(4)e35638
[http://dx.doi.org/10.1371/journal.pone.0035638] [PMID: 22558186]
[54]
Ceruti JM, Scassa ME, Fló JM, Varone CL, Cánepa ET. Induction of p19INK4d in response to ultraviolet light improves DNA repair and confers resistance to apoptosis in neuroblastoma cells. Oncogene 2005; 24(25): 4065-80.
[http://dx.doi.org/10.1038/sj.onc.1208570] [PMID: 15750620]
[55]
Sonzogni SV, Ogara MF, Castillo DS, Sirkin PF, Radicella JP, Cánepa ET. Nuclear translocation of p19INK4d in response to oxidative DNA damage promotes chromatin relaxation. Mol Cell Biochem 2015; 398(1-2): 63-72.
[http://dx.doi.org/10.1007/s11010-014-2205-1] [PMID: 25204969]
[56]
Scassa ME, Marazita MC, Ceruti JM, et al. Cell cycle inhibitor, p19INK4d, promotes cell survival and decreases chromosomal aberrations after genotoxic insult due to enhanced DNA repair. DNA Repair (Amst) 2007; 6(5): 626-38.
[http://dx.doi.org/10.1016/j.dnarep.2006.12.003] [PMID: 17218167]
[57]
Ogara MF, Belluscio LM, de la Fuente V, et al. CDK5-mediated phosphorylation of p19INK4d avoids DNA damage-induced neurodegeneration in mouse hippocampus and prevents loss of cognitive functions. Biochim Biophys Acta 2014; 1843(7): 1309-24.
[http://dx.doi.org/10.1016/j.bbamcr.2014.03.026] [PMID: 24703879]
[58]
Chen P, Zindy F, Abdala C, et al. Progressive hearing loss in mice lacking the cyclin-dependent kinase inhibitor Ink4d. Nat Cell Biol 2003; 5(5): 422-6.
[http://dx.doi.org/10.1038/ncb976] [PMID: 12717441]
[59]
Zindy F, van Deursen J, Grosveld G, Sherr CJ, Roussel MF. INK4d-deficient mice are fertile despite testicular atrophy. Mol Cell Biol 2000; 20(1): 372-8.
[http://dx.doi.org/10.1128/MCB.20.1.372-378.2000] [PMID: 10594039]
[60]
Laine H, Doetzlhofer A, Mantela J, et al. p19(Ink4d) and p21(Cip1) collaborate to maintain the postmitotic state of auditory hair cells, their codeletion leading to DNA damage and p53-mediated apoptosis. J Neurosci 2007; 27(6): 1434-44.
[http://dx.doi.org/10.1523/JNEUROSCI.4956-06.2007] [PMID: 17287518]
[61]
Hilpert M, Legrand C, Bluteau D, et al. p19 INK4d controls hematopoietic stem cells in a cell-autonomous manner during genotoxic stress and through the microenvironment during aging. Stem Cell Reports 2014; 3(6): 1085-102.
[http://dx.doi.org/10.1016/j.stemcr.2014.10.005] [PMID: 25458892]
[62]
Han X, Zhang J, Peng Y, et al. Unexpected role for p19INK4d in posttranscriptional regulation of GATA1 and modulation of human terminal erythropoiesis. Blood 2017; 129(2): 226-37.
[http://dx.doi.org/10.1182/blood-2016-09-739268] [PMID: 27879259]
[63]
Nowak D, Stewart D, Koeffler HP. Differentiation therapy of leukemia: 3 decades of development. Blood 2009; 113(16): 3655-65.
[http://dx.doi.org/10.1182/blood-2009-01-198911] [PMID: 19221035]
[64]
Matushansky I, Radparvar F, Skoultchi AI. Reprogramming leukemic cells to terminal differentiation by inhibiting specific cyclin-dependent kinases in G1. Proc Natl Acad Sci USA 2000; 97(26): 14317-22.
[http://dx.doi.org/10.1073/pnas.250488697] [PMID: 11114185]
[65]
Adachi M, Roussel MF, Havenith K, Sherr CJ. Features of macrophage differentiation induced by p19INK4d, a specific inhibitor of cyclin D-dependent kinases. Blood 1997; 90(1): 126-37.
[PMID: 9207446]
[66]
Schwaller J, Pabst T, Koeffler HP, et al. Expression and regulation of G1 cell-cycle inhibitors (p16INK4A, p15INK4B, p18INK4C, p19INK4D) in human acute myeloid leukemia and normal myeloid cells. Leukemia 1997; 11(1): 54-63.
[http://dx.doi.org/10.1038/sj.leu.2400522] [PMID: 9001419]
[67]
Sonzogni SV, Ogara MF, Belluscio LM, Castillo DS, Scassa ME, Cánepa ET. p19INK4d is involved in the cellular senescence mechanism contributing to heterochromatin formation. Biochim Biophys Acta 2014; 1840(7): 2171-83.
[http://dx.doi.org/10.1016/j.bbagen.2014.03.015] [PMID: 24667034]
[68]
Al Zaabi EA, Fernandez LA, Sadek IA, Riddell DC, Greer WL. Multiplex ligation-dependent probe amplification versus multiprobe fluorescence in situ hybridization to detect genomic aberrations in chronic lymphocytic leukemia: a tertiary center experience. J Mol Diagn 2010; 12(2): 197-203.
[http://dx.doi.org/10.2353/jmoldx.2010.090046] [PMID: 20093390]
[69]
Felisiak-Golabek A, Dansonka-Mieszkowska A, Rzepecka IK, et al. p19(INK4d) mRNA and protein expression as new prognostic factors in ovarian cancer patients. Cancer Biol Ther 2013; 14(10): 973-81.
[http://dx.doi.org/10.4161/cbt.25966] [PMID: 24022213]
[70]
Kannan K, Coarfa C, Rajapakshe K, et al. CDKN2D-WDFY2 is a cancer-specific fusion gene recurrent in high-grade serous ovarian carcinoma. PLoS Genet 2014; 10(3)e1004216
[http://dx.doi.org/10.1371/journal.pgen.1004216] [PMID: 24675677]
[71]
Lánczky A, Nagy Á, Bottai G, et al. miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients. Breast Cancer Res Treat 2016; 160(3): 439-46.
[http://dx.doi.org/10.1007/s10549-016-4013-7] [PMID: 27744485]
[72]
Li G, So AY, Sookram R, et al. Epigenetic silencing of miR-125b is required for normal B-cell development. Blood 2018; 131(17): 1920-30.
[http://dx.doi.org/10.1182/blood-2018-01-824540] [PMID: 29555645]


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VOLUME: 21
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Year: 2020
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DOI: 10.2174/1389450120666190809161901
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