Pro-apoptotic and pro-proliferation functions of the JNK pathway of Drosophila: roles in cell competition, tumorigenesis and regeneration

The Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase family. It appears to be conserved in all animal species where it regulates important physiological functions involved in apoptosis, cell migration, cell proliferation and regeneration. In this review, we focus on the functions of JNK in Drosophila imaginal discs, where it has been reported that it can induce both cell death and cell proliferation. We discuss this apparent paradox in the light of recent findings and propose that the pro-apoptotic and the pro-proliferative functions are intrinsic properties of JNK activity. Whether one function or another is predominant depends on the cellular context.

[1]  L. Johnston,et al.  Spatially Restricted Regulation of Spätzle/Toll Signaling during Cell Competition. , 2018, Developmental cell.

[2]  Chuangui Wang,et al.  HMGB1 released by irradiated tumor cells promotes living tumor cell proliferation via paracrine effect , 2018, Cell Death & Disease.

[3]  G. Morata,et al.  Short-term activation of the Jun N-terminal kinase pathway in apoptosis-deficient cells of Drosophila induces tumorigenesis , 2018, Nature Communications.

[4]  G. Morata,et al.  Distinct regenerative potential of trunk and appendages of Drosophila mediated by JNK signalling , 2017, Development.

[5]  Andrea Skinner,et al.  The Drosophila Duox maturation factor is a key component of a positive feedback loop that sustains regeneration signaling , 2017, PLoS genetics.

[6]  Rachel K. Smith-Bolton,et al.  Cap-n-Collar Promotes Tissue Regeneration by Regulating ROS and JNK Signaling in the Drosophila melanogaster Wing Imaginal Disc , 2017, Genetics.

[7]  S. Ohsawa,et al.  The ligand Sas and its receptor PTP10D drive tumour-suppressive cell competition , 2017, Nature.

[8]  B. Becattini,et al.  JNK at the crossroad of obesity, insulin resistance, and cell stress response , 2016, Molecular metabolism.

[9]  Anne-Kathrin Classen,et al.  JAK/STAT signalling mediates cell survival in response to tissue stress , 2016, Development.

[10]  I. Hariharan,et al.  Localized epigenetic silencing of a damage-activated WNT enhancer limits regeneration in mature Drosophila imaginal discs , 2016, eLife.

[11]  C. Gregory,et al.  Microenvironmental Effects of Cell Death in Malignant Disease. , 2016, Advances in experimental medicine and biology.

[12]  I. Guénal,et al.  Apoptosis in Drosophila: which role for mitochondria? , 2015, Apoptosis.

[13]  M. Savitskaya,et al.  Mechanisms of apoptosis , 2015, Biochemistry (Moscow).

[14]  M. Milán,et al.  ROS-Induced JNK and p38 Signaling Is Required for Unpaired Cytokine Activation during Drosophila Regeneration , 2015, PLoS genetics.

[15]  G. Morata,et al.  Cell competition, apoptosis and tumour development. , 2015, The International journal of developmental biology.

[16]  A. Aboobaker,et al.  JNK signalling is necessary for a Wnt- and stem cell-dependent regeneration programme , 2015, Development.

[17]  M. Plusquin,et al.  Reactive Oxygen Species in Planarian Regeneration: An Upstream Necessity for Correct Patterning and Brain Formation , 2015, Oxidative medicine and cellular longevity.

[18]  R. Paro,et al.  During Drosophila disc regeneration, JAK/STAT coordinates cell proliferation with Dilp8-mediated developmental delay , 2015, Proceedings of the National Academy of Sciences.

[19]  S. Cook,et al.  The role of MAPK signalling pathways in the response to endoplasmic reticulum stress. , 2014, Biochimica et biophysica acta.

[20]  G. Morata,et al.  Cell competition may function either as tumour-suppressing or as tumour-stimulating factor in Drosophila , 2014, Oncogene.

[21]  Kerstin Bartscherer,et al.  JNK Controls the Onset of Mitosis in Planarian Stem Cells and Triggers Apoptotic Cell Death Required for Regeneration and Remodeling , 2014, PLoS genetics.

[22]  D. Esposito,et al.  Dragging ras back in the ring. , 2014, Cancer cell.

[23]  E. Bangi,et al.  Drosophila at the intersection of infection, inflammation, and cancer , 2013, Front. Cell. Infect. Microbiol..

[24]  Sharad Kumar,et al.  Developmentally programmed cell death in Drosophila. , 2013, Biochimica et biophysica acta.

[25]  Chuan-Yuan Li,et al.  Cell death-stimulated cell proliferation: a tissue regeneration mechanism usurped by tumors during radiotherapy. , 2013, Seminars in radiation oncology.

[26]  C. Tournier The 2 Faces of JNK Signaling in Cancer. , 2013, Genes & cancer.

[27]  Mohamed Bouzaffour,et al.  Sustained production of ROS triggers compensatory proliferation and is required for regeneration to proceed , 2013, Scientific Reports.

[28]  E. Amaya,et al.  Amputation-induced reactive oxygen species (ROS) are required for successful Xenopus tadpole tail regeneration , 2013, Nature Cell Biology.

[29]  Phillip A. Newmark,et al.  The cell biology of regeneration , 2012, The Journal of cell biology.

[30]  G. Morata,et al.  A dp53/JNK-dependant feedback amplification loop is essential for the apoptotic response to stress in Drosophila , 2011, Cell Death and Differentiation.

[31]  G. Halder,et al.  Tumor suppression by cell competition through regulation of the Hippo pathway , 2011, Proceedings of the National Academy of Sciences.

[32]  H. Steller,et al.  Programmed Cell Death in Animal Development and Disease , 2011, Cell.

[33]  A. Jimeno,et al.  Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy , 2011, Nature Medicine.

[34]  G. Morata,et al.  Mitogenic signaling from apoptotic cells in Drosophila , 2011, Development, growth & differentiation.

[35]  K. Irvine,et al.  Regulation of Hippo signaling by Jun kinase signaling during compensatory cell proliferation and regeneration, and in neoplastic tumors. , 2011, Developmental biology.

[36]  K. Irvine,et al.  Warts and Yorkie Mediate Intestinal Regeneration by Influencing Stem Cell Proliferation , 2010, Current Biology.

[37]  G. Morata,et al.  A tumor-suppressing mechanism in Drosophila involving cell competition and the Hippo pathway , 2010, Proceedings of the National Academy of Sciences.

[38]  M. Corominas,et al.  Cell death-induced regeneration in wing imaginal discs requires JNK signalling , 2010, Development.

[39]  N. Xu,et al.  Paracrine unpaired signaling through the JAK/STAT pathway controls self-renewal and lineage differentiation of drosophila intestinal stem cells. , 2010, Journal of molecular cell biology.

[40]  J. C. Pastor-Pareja,et al.  Interaction between RasV12 and scribble clones induces tumour growth and invasion , 2009, Nature.

[41]  Yunbo Shi,et al.  Apoptosis in amphibian organs during metamorphosis , 2010, Apoptosis.

[42]  M. Dominguez,et al.  The position and function of the Notch‐mediated eye growth organizer: the roles of JAK/STAT and four‐jointed , 2009, EMBO reports.

[43]  J. Martinou,et al.  Apoptotic cells provide an unexpected source of Wnt3 signaling to drive hydra head regeneration. , 2009, Developmental cell.

[44]  B. Edgar,et al.  Cytokine/Jak/Stat Signaling Mediates Regeneration and Homeostasis in the Drosophila Midgut , 2009, Cell.

[45]  I. Hariharan,et al.  Regenerative growth in Drosophila imaginal discs is regulated by Wingless and Myc. , 2009, Developmental cell.

[46]  Oleg Simakov,et al.  Multiple Wnts are involved in Hydra organizer formation and regeneration. , 2009, Developmental biology.

[47]  T. Igaki Correcting developmental errors by apoptosis: lessons from Drosophila JNK signaling , 2009, Apoptosis.

[48]  Timothy J. Mitchison,et al.  A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish , 2009, Nature.

[49]  G. Morata,et al.  The role of Dpp and Wg in compensatory proliferation and in the formation of hyperplastic overgrowths caused by apoptotic cells in the Drosophila wing disc , 2009, Development.

[50]  J. C. Pastor-Pareja,et al.  Intrinsic tumor suppression and epithelial maintenance by endocytic activation of Eiger/TNF signaling in Drosophila. , 2009, Developmental cell.

[51]  Xianglin Shi,et al.  Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer. , 2009, Journal of hepatology.

[52]  J. Slack,et al.  Requirement for Wnt and FGF signaling in Xenopus tadpole tail regeneration. , 2008, Developmental biology.

[53]  O. Reiner Faculty Opinions recommendation of Beta-catenin defines head versus tail identity during planarian regeneration and homeostasis. , 2008 .

[54]  P. Reddien,et al.  Smed-βcatenin-1 Is Required for Anteroposterior Blastema Polarity in Planarian Regeneration , 2008, Science.

[55]  Jochen C. Rink,et al.  β-Catenin Defines Head Versus Tail Identity During Planarian Regeneration and Homeostasis , 2008, Science.

[56]  Kazuhiro Nakamura,et al.  The c-jun kinase/stress-activated pathway: regulation, function and role in human disease. , 2007, Biochimica et biophysica acta.

[57]  R. Moon,et al.  Wnt/beta-catenin signaling has an essential role in the initiation of limb regeneration. , 2007, Developmental biology.

[58]  R. Moon,et al.  Distinct Wnt signaling pathways have opposing roles in appendage regeneration , 2006, Development.

[59]  E. Sánchez-Herrero,et al.  Sharp boundaries of Dpp signalling trigger local cell death required for Drosophila leg morphogenesis , 2007, Nature Cell Biology.

[60]  Juan Carlos Izpisua Belmonte,et al.  Wnt/β-catenin signaling regulates vertebrate limb regeneration , 2006 .

[61]  Bostjan Kobe,et al.  Uses for JNK: the Many and Varied Substrates of the c-Jun N-Terminal Kinases , 2006, Microbiology and Molecular Biology Reviews.

[62]  I. Hariharan,et al.  Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila. , 2006, Annual review of genetics.

[63]  L. Johnston,et al.  Compensatory Proliferation in Drosophila Imaginal Discs Requires Dronc-Dependent p53 Activity , 2006, Current Biology.

[64]  M. Karin,et al.  Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[65]  T. Igaki,et al.  Loss of Cell Polarity Drives Tumor Growth and Invasion through JNK Activation in Drosophila , 2006, Current Biology.

[66]  E. Martín-Blanco,et al.  JNK signaling pathway required for wound healing in regenerating Drosophila wing imaginal discs. , 2005, Developmental biology.

[67]  G. Morata,et al.  Caspase inhibition during apoptosis causes abnormal signalling and developmental aberrations in Drosophila , 2004, Development.

[68]  Hyung Don Ryoo,et al.  Apoptotic cells can induce compensatory cell proliferation through the JNK and the Wingless signaling pathways. , 2004, Developmental cell.

[69]  E. Wagner,et al.  Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation. , 2004, Molecular cell.

[70]  M. Miura,et al.  Regulatory roles of JNK in programmed cell death. , 2004, Journal of biochemistry.

[71]  J. Mattila,et al.  Dynamics of decapentaplegic expression during regeneration of the Drosophila melanogaster wing imaginal disc. , 2004, The International journal of developmental biology.

[72]  M. Freeman,et al.  EGF receptor signalling protects smooth-cuticle cells from apoptosis during Drosophila ventral epidermis development , 2004, Development.

[73]  M. Karin,et al.  The control of cell motility and epithelial morphogenesis by Jun kinases. , 2004, Trends in cell biology.

[74]  Channing J Der,et al.  The dark side of Ras: regulation of apoptosis , 2003, Oncogene.

[75]  H. Richardson,et al.  scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila , 2003, The EMBO journal.

[76]  N. Kennedy,et al.  Role of JNK in Tumor Development , 2003, Cell cycle.

[77]  M. O’Connor,et al.  Morphogenetic apoptosis: a mechanism for correcting discontinuities in morphogen gradients. , 2002, Developmental biology.

[78]  Ginés Morata,et al.  Cells compete for Decapentaplegic survival factor to prevent apoptosis in Drosophila wing development , 2002, Nature.

[79]  I. Hickson,et al.  Cellular responses to DNA damage. , 2001, Annual review of pharmacology and toxicology.

[80]  S. Korsmeyer,et al.  The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. , 2000, Molecular cell.

[81]  R. Davis,et al.  Signal Transduction by the JNK Group of MAP Kinases , 2000, Cell.

[82]  E. Wagner,et al.  Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation , 2000, Oncogene.

[83]  D. Bar-Sagi,et al.  Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. , 2000, Science.

[84]  D. Prober,et al.  Drosophila myc Regulates Cellular Growth during Development , 1999, Cell.

[85]  J. Zeitlinger,et al.  Thorax closure in Drosophila: involvement of Fos and the JNK pathway. , 1999, Development.

[86]  E. Hafen,et al.  Autonomous Control of Cell and Organ Size by CHICO, a Drosophila Homolog of Vertebrate IRS1–4 , 1999, Cell.

[87]  Andreas Bergmann,et al.  The Drosophila Gene hid Is a Direct Molecular Target of Ras-Dependent Survival Signaling , 1998, Cell.

[88]  J. Wang,et al.  Cellular responses to DNA damage. , 1998, Current opinion in cell biology.

[89]  A. Lambertsson The minute genes in Drosophila and their molecular functions. , 1998, Advances in genetics.

[90]  E. Hafen,et al.  The Drosophila Jun-N-terminal kinase is required for cell morphogenesis but not for DJun-dependent cell fate specification in the eye. , 1996, Genes & development.

[91]  H. K. Sluss,et al.  Selective interaction of JNK protein kinase isoforms with transcription factors. , 1996, The EMBO journal.

[92]  D. Montell,et al.  Two distinct roles for Ras in a developmentally regulated cell migration. , 1996, Development.

[93]  V. Adler,et al.  UV Irradiation and Heat Shock Mediate JNK Activation via Alternate Pathways (*) , 1995, The Journal of Biological Chemistry.

[94]  H. Bourbon,et al.  hemipterous encodes a novel drosophila MAP kinase kinase, required for epithelial cell sheet movement , 1995, Cell.

[95]  I. Tsigelny,et al.  JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation. , 1994, Genes & development.

[96]  M. Karin,et al.  JNK1: A protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain , 1994, Cell.

[97]  Karl Johan Åström,et al.  Autonomous Control , 1992, 25th Anniversary of INRIA.

[98]  M. Barbacid,et al.  T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB- and Harvey-MSV transforming genes , 1982, Nature.

[99]  R. Weinberg,et al.  Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene , 1982, Nature.

[100]  C. Der,et al.  Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[101]  G. Morata,et al.  Differential mitotic rates and patterns of growth in compartments in the Drosophila wing. , 1981, Developmental biology.

[102]  P. Simpson Parameters of cell competition in the compartments of the wing disc of Drosophila. , 1979, Developmental biology.

[103]  G. Morata,et al.  Minutes: mutants of drosophila autonomously affecting cell division rate. , 1975, Developmental biology.