Abstract
The thyroid hormone (TH), 3,5,3′-triiodothyronine (T3), is an important regulator of diverse cellular processes including cell proliferation, differentiation, and apoptosis, with increasing evidence that the modulation of the phosphoproteome is an important factor in the TH-mediated response. However, little is understood regarding the mechanisms whereby phosphorylation may contribute to T3-mediated cellular outcomes during development. The cyclin-dependent kinases (Cdks) and mitogen-activated protein kinases (MAPK/ERK) have been implicated in TH signaling in mammalian cells. In this study, we have investigated, in frogs, the possible role that these kinases may have in the promotion of tail regression during tadpole metamorphosis, an important postembryonic process that is completely TH-dependent. Cdk2 steady state levels and activity increase in the tail concurrent with progression through the growth phase of metamorphosis, followed by a precipitous decrease coinciding with tail regression. Cyclin-A-associated kinase activity also follows a similar trend except that its associated kinase activity is maintained longer before a decrease in activity. Protein steady state levels of ERK1 and ERK2 remain relatively constant, and their kinase activities do not decrease until much later during tail regression. Tail tips cultured in serum-free medium in the presence of T3 undergo regression, which is accelerated by coincubation with a specific Cdk2 inhibitor. Coincubation with PD098059, a MAPK inhibitor, has no effect. Thus, T3-dependent tail regression does not require MAPKs, but a decrease in Cdk2 activity promotes tail regression.
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Adachi S, Ito H, Tamamori-Adachi M, Ono Y, Nozato T, Abe S, Ikeda M, Marumo F, Hiroe M (2001) Cyclin A/cdk2 activation is involved in hypoxia-induced apoptosis in cardiomyocytes. Circ Res 88:408–414
Alessi DR, Quarta S, Savio M, Riva F, Rossi L, Stivala L, Scovassi A, Meijer L, Prosperi E (1998) The cyclin-dependent kinase inhibitors olomoucine and roscovitine arrest human fibroblasts in G1 phase by specific inhibition of CDK2 kinase activity. Exp Eye Res 245:8–18
Alisi A, Demori I, Spagnuolo S, Pierantozzi E, Fugassa E, Leoni S (2005) Thyroid status affects rat liver regeneration after partial hepatectomy by regulating cell cycle and apoptosis. Cell Physiol Biochem 15:69–76
Barrera-Hernandez G, Park K, Dace A, Zhan Q, Cheng S-Y (1999) Thyroid hormone-induced cell proliferation in GC cells is mediated by changes in G1 cyclin/cyclin-dependent kinase levels and activity. Endocrinology 140:5267–5274
Bassett J, Harvey CB, Williams GR (2003) Mechanisms of thyroid hormone receptor-specific nuclear and extra nuclear actions. Mol Cell Endocrinol 213:1–11
Bortner D, Rosenberg M (1995) Overexpression of cyclin A in the mammary glands of transgenic mice results in the induction of nuclear abnormalities and increased apoptosis. Cell Growth Differ 6:1579–1589
Brown G, Hughes P, Michell R (2003) Cell differentiation and proliferation—simultaneous but independent? Exp Cell Res 291:282–288
Buchholz DR, Hsia SC, Fu L, Shi YB (2003) A dominant-negative thyroid hormone receptor blocks amphibian metamorphosis by retaining corepressors at target genes. Mol Cell Biol 23:6750–6758
Buchholz DR, Tomita A, Fu L, Paul BD, Shi YB (2004) Transgenic analysis reveals that thyroid hormone receptor is sufficient to mediate the thyroid hormone signal in frog metamorphosis. Mol Cell Biol 24:9026–9037
Buzzard JJ, Wreford NG, Morrison JR (2003) Thyroid hormone, retinoic acid, and testosterone suppress proliferation and induce markers of differentiation in cultured Sertoli cells. Endocrinology 144:3722–3731
Chen S, Chang Y, Wu Y, Lin K (2003) Mitogen-activated protein kinases potentiate thyroid hormone receptor transcriptional activity by stabilizing its protein. Endocrinology 144:1407–1419
Das B, Cai L, Carter M, Piao Y-L, Sharov A, Ko M, Brown DD (2006) Gene expression changes at metamorphosis induced by thyroid hormone in Xenopus laevis. Dev Biol 291:342–355
Davis PJ, Davis FB, Cody V (2005) Membrane receptors mediating thyroid hormone action. Trends Endocrinol Metab 16:429–435
Dobashi Y, Shoji M, Kondo E, Akiyama T, Kameya T (1998) CDK4, a possible critical regulator of apoptosis in rat pheochromocytoma PC12 cells. Biochem Biophys Res Commun 253:609–613
Gil-Gomez G, Berns A, Brady H (1998) A link between cell cycle and cell death: bax and Bcl-2 modulate Cdk2 activation during thymocyte apoptosis. EMBO J 17:7209–7218
Hajduch M, Havlieek L, Vesely J, Novotny R, Mihal V, Strnad M (1999) Synthetic cyclin dependent kinase inhibitors. New generation of potent anti-cancer drugs. Adv Exp Med Biol 457:341–353
Harvey C, Williams G (2002) Mechanism of thyroid hormone action. Thyroid 12:441–446
Helbing CC, Atkinson BG (1994) 3,5,3′-Triiodothyronine-induced carbamyl phosphate synthetase gene expression is stabilized in the liver of Rana catesbeiana tadpoles during heat shock. J Biol Chem 269:11743–11750
Helbing CC, Gergely G, Atkinson BG (1992) Sequential up-regulation of thyroid hormone β receptor, ornithine transcarbamylase and carbamyl phosphate synthetase mRNAs in the liver of Rana catesbeiana tadpoles during spontaneous and thyroid hormone-induced metamorphosis. Dev Genet 13:289–301
Helbing C, Gallimore C, Atkinson BG (1996) Characterization of a Rana catesbeiana Hsp30 gene and its expression in the liver of this amphibian during both spontaneous and thyroid hormone-induced metamorphosis. Dev Genet 18:223–233
Helbing CC, Wellington CL, Gogela-Spehar M, Cheng T, Pinchbeck G, Johnston RN (1998) Quiescence versus apoptosis: Myc abundance determines pathway of exit from the cell cycle. Oncogene 17:1491–1501
Helbing C, Werry K, Crump D, Domanski D, Veldhoen N, Bailey C (2003) Expression profiles of novel thyroid hormone-responsive genes and proteins in the tail of Xenopus laevis tadpoles undergoing precocious metamorphosis. Mol Endocrinol 17:1395–1409
Hirai H, Kawanishi N, Iwasawa Y (2005) Recent advances in the development of selective small molecule inhibitors for cyclin-dependent kinases. Curr Top Med Chem 5:167–179
Hoang AT, Cohen KJ, Barrett JF, Bergstrom DA, Dang CV (1994) Participation of cyclin A in Myc-induced apoptosis. Proc Natl Acad Sci USA 91:6875–6879
Holsberger D, Cooke P (2005) Understanding the role of thyroid hormone in Sertoli cell development: a mechanistic hypothesis. Cell Tissue Res 322:133–140
Holsberger DR, Jirawatnotai S, Kiyokawa H, Cooke PS (2003) Thyroid hormone regulates the cell cycle inhibitor p27Kip1 in postnatal murine Sertoli cells. Endocrinology 144:3732–3738
Holsberger D, Buchold G, Leal M, Kiesewetter S, O’Brien D, Hess R, Franca L, Kiyokawa H, Cooke P (2005) Cell-cycle inhibitors p27Kip1 and p21Cip1 regulate murine Sertoli cell proliferation. Biol Reprod 72:1429–1436
Jones K, Brubaker J, Chin WW (1994) Evidence that phosphorylation events participate in thyroid hormone action. Endocrinology 134:543–548
Kanamori A, Brown D (1993) Cultured cells as a model for amphibian metamorphosis. Proc Natl Acad Sci USA 90:6013–6017
Kondoh K, Torii S, Nishida E (2005) Control of MAP kinase signaling to the nucleus. Chromosoma 114:86–91
Kuno-Murata M, Koibuchi N, Fukuda H, Murata M, Chin WW (2000) Augmentation of thyroid hormone receptor-mediated transcription by Ca2+/calmodulin-dependent protein kinase type IV. Endocrinology 141:2275–2278
Laemmli U (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685
Levkau B, Koyama H, Rains E, Clurman B, Herren B, Orth K, Roberts J, Ross R (1998) Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade. Mol Cell 1:553–563
Meijer L, Borgne A, Mulner O, Chong J, Blow J, Inagki N, Inagaki M, Delcros J, Moulinoux J (1997) Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem 243:527–536
Meikrantz W, Schlegel R (1996) Suppression of apoptosis by dominant negative mutants of cyclin-dependent protein kinases. J Biol Chem 271:10205–10209
Meikrantz W, Gisselbrecht S, Tam SW, Schlegel R (1994) Activation of cyclin A-dependent protein kinases during apoptosis. Proc Natl Acad Sci USA 91:3754–3758
Miller LD, Park KS, Guo QM, Alkharouf NW, Malek RL, Lee NH, Liu ET, Cheng S-Y (2001) Silencing of Wnt signaling and activation of multiple metabolic pathways in response to thyroid hormone-stimulated cell proliferation. Mol Cell Biol 21:6626–6639
Minshull J, Sun H, Tonks NK, Murray AW (1994) A MAP kinase-dependent spindle assembly checkpoint in Xenopus egg extracts. Cell 79:475–486
Oppenheimer J (1999) Evolving concepts of thyroid hormone action. Biochimie 81:539–543
Panka D, Atkins MB, Mier JW (2006) Targeting the mitogen-activated protein kinase pathway in the treatment of malignant melanoma. Clin Cancer Res 12:2371s–2375s
Park DS, Morris EJ, Padmanabhan J, Shelanski ML, Geller HM, Greene LA (1998) Cyclin-dependent kinases participate in death of neurons evoked by DNA-damaging agents. J Cell Biol 143:457–467
Pestell R, Albenese C, Reutens A, Segall J, Lee R, Arnold A (1999) The cyclins and cyclin-dependent kinase inhibitors in hormonal regulation of proliferation and differentiation. Endocr Rev 20:501–534
Puzianowska-Kuznicka M, Wong J, Kanamori A, Shi Y (1996) Functional characterization of a mutant thyroid hormone receptor in Xenopus laevis. J Biol Chem 271:33394–33403
Regard E, Taurog A, Nakashima T (1978) Plasma thyroxine and triiodothyronine levels in spontaneously metamorphosing Rana catesbeiana tadpoles and in adult anuran amphibia. Endocrinology 102:674–684
Rosenfeld MG, Glass CK (2001) Coregulator codes of transcriptional regulation by nuclear receptors. J Biol Chem 276:36865–36868
Sausville E (2002) Complexities in the development of cyclin-dependent kinase inhibitor drugs. Trends Mol Med 8:S32–S37
Schreiber AM, Das B, Huang H, Marsh-Armstrong N, Brown DD (2001) Diverse developmental programs of Xenopus laevis metamorphosis are inhibited by a dominant negative thyroid hormone receptor. Proc Natl Acad Sci USA 98:10739–10744
Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512
Sherr C, Roberts J (2004) Living with or without cyclins and cyclin dependent kinases. Genes Dev 18:2699–2711
Shi Y-B (2000) Amphibian metamorphosis: from morphology to molecular biology. Wiley-Liss, New York
Shi L, Nishioka WK, Th’ng J, Bradbury EM, Litchfield DW, Greenberg AH (1994) Premature p34cdc2 activation required for apoptosis. Science 263:1143–1145
Taylor AC, Kollros JJ (1946) Stages in the normal development of Rana pipiens larvae. Anat Rec 94:7–24
Ting Y-T, Bhat MK, Wong R (1997) Tissue-specific stabilization of the thyroid hormone beta1 nuclear receptor by phosphorylation. J Biol Chem 272:4129–4134
Tzagarakis-Foster C, Privalsky M (1998) Phosphorylation of thyroid hormone receptors by protein kinase A regulates DNA recognition by specific inhibition of receptor monomer binding. J Biol Chem 273:10926–10932
Veldhoen N, Crump D, Werry K, Helbing C (2002) Distinctive gene profiles occur at key points during natural metamorphosis in the Xenopus laevis tadpole tail. Dev Dyn 225:457–468
Veldhoen N, Skirrow R, Ji L, Domanski D, Bonfield E, Bailey C, Helbing C (2006) Use of heterologous cDNA arrays and organ culture in the detection of thyroid hormone-dependent responses in a sentinel frog, Rana catesbeiana. Comp Biochem Physiol [D] 1:187–199
Wagner MJ, Gogela-Spehar M, Skirrow RC, Johnston RN, Riabowol K, Helbing CC (2001) Expression of novel ING variants is regulated by thyroid hormone in the Xenopus laevis tadpole. J Biol Chem 276:47013–47020
White BA, Nicoll CS (1981) Hormonal control of amphibian metamorphosis. In: Gilbert LI, Frieden E (eds) Metamorphosis: a problem in developmental biology. Plenum, New York, pp 363–396
Wood WM, Sarapura VD, Dowding JM, Woodmansee WW, Haakinson DJ, Gordon DF, Ridgway EC (2002) Early gene expression changes preceding thyroid hormone-induced involution of a thyrotrope tumor. Endocrinology 143:347–359
Yao S, McKenna K, Sharkis S, Bedi A (1996) Requirement of p34cdc2 kinase for apoptosis mediated by the Fas/APO-1 receptor and interleukin 1beta-converting enzyme-related proteases. Cancer Res 56:4551–4555
Yen C, Huang Y, Liao C, Liao C, Cheng W, Chen W, Lin K (2006) Mediation of the inhibitory effect of thyroid hormone on proliferation of hepatoma cells by transforming growth factor-beta. J Mol Endocrinol 36:9–21
Yen PM (2001) Physiological and molecular basis of thyroid hormone action. Physiol Rev 81:1097–1142
Zhang J, Lazar M (2000) The mechanism of action of thyroid hormones. Annu Rev Physiol 62:439–466
Acknowledgments
We thank D. Domanski for expert technical support and Dr. N. Veldhoen, D. Domanski, M.J. Wagner, C. Bailey, L. Ji, and Dr. F. Zhang for helpful discussions and critical reading of the manuscript. We are grateful to T. Hunt at the Imperial Cancer Research Fund, UK, for providing the cyclin A2 antibody. C.C.H. would like to acknowledge Dr. K.Y. Lee, University of Calgary, for his kinase assay expertise in the early stages of this investigation.
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This work was supported by a NSERC operating grant, NSERC University Faculty Award, and Michael Smith Foundationfor Health Research Scholar Award.
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Skirrow, R.C., Helbing, C.C. Decreased cyclin-dependent kinase activity promotes thyroid hormone-dependent tail regression in Rana catesbeiana . Cell Tissue Res 328, 281–289 (2007). https://doi.org/10.1007/s00441-006-0362-6
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DOI: https://doi.org/10.1007/s00441-006-0362-6