Abstract
The serine/threonine kinase Mirk is an active kinase in pancreatic, ovarian and colon cancers, but is not activated by mutation. Mirk was upregulated or amplified in the majority of resected pancreatic or ovarian adenocarcinomas, and may be selected for by enabling cancer cells to enter a reversible quiescent state and thus survive suboptimal conditions. Mirk/dyrk1B levels and activity are highest when cells are quiescent. Some cancer cells can enter a reversible quiescent phase dependent on p130/Rb2 and Mirk/dyrk1B when deprived of growth factors, while others undergo autophagy or apoptosis. Mirk blocks cell cycle progression in G0 by complexing with GSK3ß and destabilizing cyclin D isoforms and by activating by phosphorylation Lin52, which is part of the DREAM complex including p130/Rb2 which sequesters E2F4 and other transcription factors necessary for cells to enter cycle. Mirk transcriptional co-activator activity allows Mirk to decrease ROS levels by increasing expression of a group of antioxidant genes. Since Mirk is activated by oncogenic K-ras/H-ras, its upregulation of antioxidant genes may compensate for the increase in ROS induced by ras oncoproteins. Mirk competes with the SAPK p38 for binding to their common activator MKK3. Thus Mirk is upregulated or amplified in certain pancreatic and ovarian cancers, is an active kinase in these cancers, and under suboptimal growth conditions, maintains these cancer cells in a viable, quiescent state.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Adam AP, George A, Schewe D, Bragado P, Iglesias BV, Ranganathan AC, Kourtidis A, Conklin DS, Aguirre-Ghiso JA (2009) Computational identification of a p38SAPK-regulated transcription factor network required for tumor cell quiescence. Cancer Res 69:5664–5672
Chen C, Liu Y, Liu R, Ikenoue T, Guan K-L, Liu Y, Zheng P (2008) TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med 205:2397–2408
Coller H, Sang L, Roberts JM (2006) A new description of cellular quiescence. PLoS Biol 4:329–349
D’Andrilli G, Masciullo V, Bagella L, Tonini T, Minimo C, Zannoni GF, Giuntoli RL II, Carlson JA Jr, Soprano DR, Soprano KJ, Scambia G, Giordano A (2004) Frequent loss of pRb2/p130 in human ovarian carcinoma. Clin Cancer Res 10:3098–3103
Deng X, Mercer SE, Shah S, Ewton DZ, Friedman E (2004) The cyclin-dependent kinase inhibitor p27kip1 is stabilized in G0 by Mirk/dyrk1b kinase. J Biol Chem 279:22498–22504
Deng X, Ewton DZ, Li S, Naqvi A, Mercer SE, Landas S, Friedman E (2006) The kinase Mirk/Dyrk1B mediates cell survival in pancreatic ductal adenocarcinoma. Cancer Res 66:4149–4158
Deng X, Ewton DZ, Friedman E (2009) Mirk/Dyrk1B maintains the viability of quiescent pancreatic cancer cells by decreasing ROS levels. Cancer Res 69:3317–3324
Ewton D, Hu J, Vilenchik M, Deng X, Luk K-C, Polonskaia A, Hoffman A, Zipf K, Heimbrook D, Boylan J, Friedman E (2011) Inactivation of Mirk/dyrk1b kinase targets quiescent pancreatic cancer cells. Mol Cancer Ther 10:2104–2114
Friedman E (2007) Mirk/dyrk1B in cancer. J Cell Biochem 102:274–279
Germain D, Russell A, Thompson A, Hendley J (2000) Ubiquitination of free cyclin D1 is independent of phosphorylation on threonine 286. J Biol Chem 275:12074–12079
Hu J, Friedman E (2010) Depleting Mirk kinase increases cisplatin toxicity in ovarian cancer cells. Genes Cancer 1:803–811
Hu J, Nakhla H, Friedman E (2011) Mirk/dyrk1B and p130/Rb2 mediate quiescence in ovarian cancer cells. Int J Cancer 129:307–318
Jin K, Lim S, Mercer SE, Friedman E (2005) The survival kinase Mirk/dyrk1B is activated through Rac1-MKK3 signaling. J Biol Chem 280:42097–42105
Jin K, Park S-J, Ewton D, Friedman E (2007) The survival kinase Mirk/dyrk1B is a downstream effector of oncogenic K-ras. Cancer Res 67:7247–7255
Jin K, Ewton D, Park S, Hu J, Friedman E (2009) Mirk regulates the exit of colon cancer cells from quiescence. J Biol Chem 284:22916–22925
Karhu R, Mahlamaki E, Kallioniemi A (2006) Pancreatic adenocarcinoma- genetic portrait from chromosomes to microarrays. Genes Chromosomes Cancer 45:721–730
Kops G, Dansen TB, Polderman PE, Saarloos I, Wirtz KWA, Coffer PJ, Huang T-T, Bos JL, Medema RH, Burgering BMT (2002) Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419:316
Kuuselo R, Savinainen K, Azorsa DO, Basu GD, Karhu R, Tuzmen S, Mousses S, Kallioniemi A (2007) Intersex-like (IXL) is a cell survival regulator in pancreatic cancer with 19q13 amplification. Cancer Res 67:1943–1949
Kuuselo R, Simon R, Karhu R, Tennstedt P, Marx AH, Izbicki JR, Yekebas E, Sauter G, Kallioniemi A (2010) 19q13 amplification is associated with high grade and stage in pancreatic cancer. Genes Chromosomes Cancer 49:569–575
Lauth M, Bergstrom A, Shimokawa T, Tostar U, Jin Q, Fendrich V, Guerra C, Barbacid M, Toftgard R (2010) DYRK1B-dependent autocrine-to-paracrine shift of Hedgehog signaling by mutant RAS. Nat Struct Mol Biol 17:718–725
Leder S, Czajkowska H, Maenz B, de Graaf K, Barthel A, Joost H-G, Becker W (2003) Alternative splicing variants of the protein kinase DYRK1B exhibit distinct patterns of expression and functional properties. Biochem J 372:881–888
Lee K, Deng X, Friedman E (2000) Mirk protein kinase is a mitogen-activated protein kinase substrate that mediates survival of colon cancer cells. Cancer Res 60:3631–3637
Lim S, Jin K, Friedman E (2002a) Mirk protein kinase is activated by MKK3 and functions as a transcriptional activator of HNF1alpha. J Biol Chem 277:25040–25046
Lim S, Zou Y, Friedman E (2002b) The transcriptional activator Mirk/Dyrk1B is sequestered by p38alpha/beta MAP Kinase. J Biol Chem 277:49438–49445
Litovchick L, Florens LA, Swanson SK, Washburn MP, DeCaprio JA (2011) DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes Dev 25:801–813
Schindlbeck C, Hantschmann P, Zerzer M, Jahns B, Rjosk D, Janni W, Rack B, Sommer H, Friese K (2007) Prognostic impact of KI67, p53, human epithelial growth factor receptor 2, topoisomerase IIalpha, epidermal growth factor receptor, and nm23 expression of ovarian carcinomas and disseminated tumor cells in the bone marrow. Int J Gynecol Cancer 17(5):1047–1055
Smith E, Leone G, Nevins J (1998) Distinct mechanisms control the accumulation of the Rb-related p107 and p130 proteins during cell growth. Cell Growth Differ 9:297–303
Sosa MS, Avivar-Valderas A, Bragado P, Wen H-C, Aguirre-Ghiso JA (2011) ERK1/2 and p38 signaling in tumor cell quiescence: opportunities to control dormant residual disease. Clin Cancer Res 17:5850–5857
Stanton KJ, Sidner RA, Miller GA, Cummings OW, Schmidt CM, Howard TJ, Wiebke EA (2003) Analysis of Ki-67 antigen expression, DNA proliferative fraction, and survival in resected cancer of the pancreas. Am J Surg 186:486–492
Thompson FH, Nelson MA, Trent JM, Guan X-Y, Liu Y, Yang J-M, Emerson J, Adair L, Wymer J, Balfour C, Massey K, Weinstein R, Alberts DS, Taetle R (1996) Amplification of 19q13.1-q13.2 sequences in ovarian cancer: G-band, FISH, and molecular studies. Cancer Genet Cytogenet 87:55
Trachootham D, Zhou Y, Zhang H, Demizu Y, Chen Z, Pelicano H, Chiao P, Achanta G, Arlinghaus R, Liu J, Huang P (2006) Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by β-phenylethyl isothiocyanate. Cancer Cell 10:241–252
Zou Y, Ewton D, Deng D, Mercer S, Friedman E (2004) Mirk/dyrk1B kinase destabilizes cyclin D1 by phosphorylation at threonine 288. J Biol Chem 279:27790–27798
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Friedman, E.A. (2013). The Kinase MIRK/DYRK1B Mediates a Reversible Quiescent State in a Subset of Ovarian, Pancreatic and Colon Cancers. In: Hayat, M. (eds) Tumor Dormancy, Quiescence, and Senescence, Volume 1. Tumor Dormancy and Cellular Quiescence and Senescence, vol 1. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5958-9_10
Download citation
DOI: https://doi.org/10.1007/978-94-007-5958-9_10
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-5957-2
Online ISBN: 978-94-007-5958-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)