Post-transcriptional regulation of the Ras-ERK/MAPK signaling pathway

Journal of Cellular Physiology

Volumn 227, Issue 3, 2012, Pages 1235-1241

  Whelan, Jarrett T ^a   Hollis, Sarah E ^a   Cha, Dong Seok ^a   Asch, Adam S ^a,b   Lee, Myon Hee ^a,b  

^a EAST CAROLINA UNIVERSITY   (United States)

^b UNIVERSITY OF NORTH CAROLINA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CAENORHABDITIS ELEGANS PROTEIN; DUAL SPECIFICITY PHOSPHATASE 6; HU ANTIGEN; MICRORNA; MITOGEN ACTIVATED PROTEIN KINASE; PUMILIOTOXIN; RNA BINDING PROTEIN;

BINDING KINETICS; CANCER CELL; CARCINOGENESIS; CELL DIFFERENTIATION; CELL FATE; CELL GROWTH; CELL PROLIFERATION; CELL SURVIVAL; EUKARYOTIC CELL; HOMEOSTASIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; RECEPTOR DOWN REGULATION; RNA STABILITY; SHORT SURVEY; SIGNAL TRANSDUCTION; STEM CELL; TRANSCRIPTION REGULATION;

EXTRACELLULAR SIGNAL-REGULATED MAP KINASES; HUMANS; MAP KINASE SIGNALING SYSTEM; MITOGEN-ACTIVATED PROTEIN KINASES; NEOPLASMS; RAS PROTEINS; RNA-BINDING PROTEINS; TRANSCRIPTION, GENETIC;

EID: 84155192294     PISSN: 00219541     EISSN: 10974652     Source Type: Journal    
DOI: 10.1002/jcp.22899     Document Type: Short Survey

References (102)

1. Abdelmohsen K, Lal A, Kim HH, Gorospe M. 2007. Posttranscriptional orchestration of an anti-apoptotic program by HuR. Cell Cycle 6: 1288-1292.
2. Ambros V. 2004. The functions of animal microRNAs. Nature 431: 350-355.
3. Armstrong L, Hughes O, Yung S, Hyslop L, Stewart R, Wappler I, Peters H, Walter T, Stojkovic P, Evans J, Stojkovic M, Lako M. 2006. The role of PI3K/AKT, MAPK/ERK and NFkappabeta signalling in the maintenance of human embryonic stem cell pluripotency and viability highlighted by transcriptional profiling and functional analysis Hum Mol Genet 15: 1894-1913.
4. Bandziulis RJ, Swanson MS, Dreyfuss G. 1989. RNA-binding proteins as developmental regulators. Genes Dev 3: 431-437.
5. Bayfield MA, Yang R, Maraia RJ. 2010. Conserved and divergent features of the structure and function of La and La-related proteins (LARPs). Biochim Biophys Acta 1799: 365-378.
6. Bermudez O, Jouandin P, Rottier J, Bourcier C, Pages G, Gimond C. 2011. Post-transcriptional regulation of the DUSP6/MKP-3 phosphatase by MEK/ERK signaling and hypoxia. J Cell Physiol 226: 276-284.
7. Biedermann B, Wright J, Senften M, Kalchhauser I, Sarathy G, Lee MH, Ciosk R. 2009. Translational repression of cyclin E prevents precocious mitosis and embryonic gene activation during C. elegans meiosis. Dev Cell 17: 355-364.
8. Blaxall BC, Dwyer-Nield LD, Bauer AK, Bohlmeyer TJ, Malkinson AM, Port JD. 2000. Differential expression and localization of the mRNA binding proteins, AU-rich element mRNA binding protein (AUF1) and Hu antigen R (HuR), in neoplastic lung tissue. Mol Carcinog 28: 76-83.
9. Boyerinas B, Park SM, Hau A, Murmann AE, Peter ME. 2010. The role of let-7 in cell differentiation and cancer. Endocr Relat Cancer 17: F19-F36.
10. Brennan CM, Steitz JA. 2001. HuR and mRNA stability. Cell Mol Life Sci 58: 266-277.
11. Brondello JM, Pouyssegur J, McKenzie FR. 1999. Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. Science 286: 2514-2517.
12. Burdon T, Smith A, Savatier P. 2002. Signalling, cell cycle and pluripotency in embryonic stem cells. Trends Cell Biol 12: 432-438.
13. Camps M, Nichols A, Arkinstall S. 2000. Dual specificity phosphatases: A gene family for control of MAP kinase function. FASEB J 14: 6-16.
14. Carrington JC, Ambros V. 2003. Role of microRNAs in plant and animal development. Science 301: 336-338.
15. Cassar PA, Stanford WL. 2011. Integrating post-transcriptional regulation into the embryonic stem cell gene regulatory network. J Cell Physiol [Epub ahead of print] DOI: 10.1002/jcp.22787.
16. Castelli M, Camps M, Gillieron C, Leroy D, Arkinstall S, Rommel C, Nichols A. 2004. MAP kinase phosphatase 3 (MKP3) interacts with and is phosphorylated by protein kinase CK2alpha. J Biol Chem 279: 44731-44739.
17. Chen T, Kurjan J. 1997. Saccharomyces cerevisiae Mpt5p interacts with Sst2p and plays roles in pheromone sensitivity and recovery from pheromone arrest. Mol Cell Biol 17: 3429-3439.
18. Cherry J, Karschner V, Jones H, Pekala PH. 2006. HuR, an RNA-binding protein, involved in the control of cellular differentiation. In Vivo 20: 17-23.
19. Crittenden SL, Bernstein DS, Bachorik JL, Thompson BE, Gallegos M, Petcherski AG, Moulder G, Barstead R, Wickens M, Kimble J. 2002. A conserved RNA-binding protein controls germline stem cells in Caenorhabditis elegans. Nature 417: 660-663.
20. Danilin S, Sourbier C, Thomas L, Lindner V, Rothhut S, Dormoy V, Helwig JJ, Jacqmin D, Lang H, Massfelder T. 2010. Role of the RNA-binding protein HuR in human renal cell carcinoma. Carcinogenesis 31: 1018-1026.
21. de Andres-Aguayo L, Varas F, Kallin EM, Infante JF, Wurst W, Floss T, Graf T. 2011. Musashi 2 is a regulator of the hematopoietic stem cell compartment identified by a retroviral insertion screen and knockout mice. Blood
22. Denkert C, Koch I, von Keyserlingk N, Noske A, Niesporek S, Dietel M, Weichert W. 2006. Expression of the ELAV-like protein HuR in human colon cancer: Association with tumor stage and cyclooxygenase-2. Mod Pathol 19: 1261-1269.
23. Doller A, Pfeilschifter J, Eberhardt W. 2008. Signalling pathways regulating nucleo-cytoplasmic shuttling of the mRNA-binding protein HuR. Cell Signal 20: 2165-2173.
24. Eblaghie MC, Lunn JS, Dickinson RJ, Munsterberg AE, Sanz-Ezquerro JJ, Farrell ER, Mathers J, Keyse SM, Storey K, Tickle C. 2003. Negative feedback regulation of FGF signaling levels by Pyst1/MKP3 in chick embryos. Curr Biol 13: 1009-1018.
25. Echevarria D, Martinez S, Marques S, Lucas-Teixeira V, Belo JA. 2005. Mkp3 is a negative feedback modulator of Fgf8 signaling in the mammalian isthmic organizer. Dev Biol 277: 114-128.
26. Eckmann CR, Crittenden SL, Suh N, Kimble J. 2004. GLD-3 and control of the mitosis/meiosis decision in the germline of Caenorhabditis elegans. Genetics 168: 147-160.
27. Erkinheimo TL, Lassus H, Sivula A, Sengupta S, Furneaux H, Hla T, Haglund C, Butzow R, Ristimaki A. 2003. Cytoplasmic HuR expression correlates with poor outcome and with cyclooxygenase 2 expression in serous ovarian carcinoma. Cancer Res 63: 7591-7594.
28. Forbes A, Lehmann R. 1998. Nanos and Pumilio have critical roles in the development and function of Drosophila germline stem cells. Development 125: 679-690.
29. Francis R, Barton MK, Kimble J, Schedl T. 1995. gld-1, a tumor suppressor gene required for oocyte development in Caenorhabditis elegans. Genetics 139: 579-606.
30. Furukawa T, Sunamura M, Motoi F, Matsuno S, Horii A. 2003. Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer. Am J Pathol 162: 1807-1815.
31. Galgano A, Forrer M, Jaskiewicz L, Kanitz A, Zavolan M, Gerber AP. 2008. Comparative analysis of mRNA targets for human PUF-family proteins suggests extensive interaction with the miRNA regulatory system. PLoS One 3: e3164.
32. Geest CR, Coffer PJ. 2009. MAPK signaling pathways in the regulation of hematopoiesis. J Leukoc Biol 86: 237-250.
33. Gerber AP, Herschlag D, Brown PO. 2004. Extensive association of functionally and cytotopically related mRNAs with Puf family RNA-binding proteins in yeast. PLoS Biol 2: E79.
34. Gerber AP, Luschnig S, Krasnow MA, Brown PO, Herschlag D. 2006. Genome-wide identification of mRNAs associated with the translational regulator PUMILIO in Drosophila melanogaster. Proc Natl Acad Sci USA 103: 4487-4492.
35. Ghosh M, Aguila HL, Michaud J, Ai Y, Wu MT, Hemmes A, Ristimaki A, Guo C, Furneaux H, Hla T. 2009. Essential role of the RNA-binding protein HuR in progenitor cell survival in mice. J Clin Invest 119: 3530-3543.
36. Gibson TJ, Thompson JD, Heringa J. 1993. The KH domain occurs in a diverse set of RNA-binding proteins that include the antiterminator NusA and is probably involved in binding to nucleic acid. FEBS Lett 324: 361-366.
37. Goldstrohm AC, Hook BA, Seay DJ, Wickens M. 2006. PUF proteins bind Pop2p to regulate messenger RNAs. Nat Struct Mol Biol 13: 533-539.
38. Groom LA, Sneddon AA, Alessi DR, Dowd S, Keyse SM. 1996. Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel cytosolic dual-specificity phosphatase. EMBO J 15: 3621-3632.
39. Heinonen M, Bono P, Narko K, Chang SH, Lundin J, Joensuu H, Furneaux H, Hla T, Haglund C, Ristimaki A. 2005. Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinoma. Cancer Res 65: 2157-2161.
40. Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ. 2005. RAS is regulated by the let-7 microRNA family. Cell 120: 635-647.
41. Jurek A, Amagasaki K, Gembarska A, Heldin CH, Lennartsson J. 2009. Negative and positive regulation of MAPK phosphatase 3 controls platelet-derived growth factor-induced Erk activation. J Biol Chem 284: 4626-4634.
42. Kaeberlein M, Guarente L. 2002. Saccharomyces cerevisiae MPT5 and SSD1 function in parallel pathways to promote cell wall integrity. Genetics 160: 83-95.
43. Kennedy BK, Austriaco NR Jr, Zhang J, Guarente L. 1995. Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae. Cell 80: 485-496.
44. Kennedy BK, Gotta M, Sinclair DA, Mills K, McNabb DS, Murthy M, Pak SM, Laroche T, Gasser SM, Guarente L. 1997. Redistribution of silencing proteins from telomeres to the nucleolus is associated with extension of life span in S. cerevisiae. Cell 89: 381-391.
45. Kershner AM, Kimble J. 2010. Genome-wide analysis of mRNA targets for Caenorhabditis elegans FBF, a conserved stem cell regulator. Proc Natl Acad Sci USA 107: 3936-3941.
46. Kikuchi Y, Oka Y, Kobayashi M, Uesono Y, Toh-e A, Kikuchi A. 1994. A new yeast gene, HTR1, required for growth at high temperature, is needed for recovery from mating pheromone-induced G1 arrest. Mol Gen Genet 245: 107-116.
47. Kumar MS, Erkeland SJ, Pester RE, Chen CY, Ebert MS, Sharp PA, Jacks T. 2008. Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci USA 105: 3903-3908.
48. Kuwano Y, Gorospe M. 2008. Protecting the stress response, guarding the MKP-1 mRNA. Cell Cycle 7: 2640-2642.
49. Kuwano Y, Kim HH, Abdelmohsen K, Pullmann R Jr, Martindale JL, Yang X, Gorospe M. 2008. MKP-1 mRNA stabilization and translational control by RNA-binding proteins HuR and NF90. Mol Cell Biol 28: 4562-4575.
50. Lamont LB, Crittenden SL, Bernstein D, Wickens M, Kimble J. 2004. FBF-1 and FBF-2 regulate the size of the mitotic region in the C. elegans germline. Dev Cell 7: 697-707.
51. Lee MH, Hook B, Lamont LB, Wickens M, Kimble J. 2006. LIP-1 phosphatase controls the extent of germline proliferation in Caenorhabditis elegans. EMBO J 25: 88-96.
52. Lee MH, Hook B, Pan G, Kershner AM, Merritt C, Seydoux G, Thomson JA, Wickens M, Kimble J. 2007a. Conserved regulation of MAP kinase expression by PUF RNA-binding proteins. PLoS Genet 3: e233.
53. Lee MH, Ohmachi M, Arur S, Nayak S, Francis R, Church D, Lambie E, Schedl T. 2007b. Multiple functions and dynamic activation of MPK-1 extracellular signal-regulated kinase signaling in Caenorhabditis elegans germline development. Genetics 177: 2039-2062.
54. Lee MH, Schedl T. 2001. Identification of in vivo mRNA targets of GLD-1, a maxi-KH motif containing protein required for C. elegans germ cell development. Genes Dev 15: 2408-2420.
55. Lee MH, Schedl T. 2004. Translation repression by GLD-1 protects its mRNA targets from nonsense-mediated mRNA decay in C. elegans. Genes Dev 18: 1047-1059.
56. Lee MH, Schedl T. 2006. RNA-binding proteins. WormBook. 1-13.
57. Lee MH, Won Kim K, Morgan CT, Morgan DE, Kimble J. 2011. Phosphorylation state of a Tob/BTG protein, FOG-3, regulates initiation and maintenance of the Caenorhabditis elegans sperm fate program. Proc Natl Acad Sci USA 108: 9125-9130.
58. Lee RC, Feinbaum RL, Ambros V. 1993. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75: 843-854.
59. Li C, Scott DA, Hatch E, Tian X, Mansour SL. 2007. Dusp6 (Mkp3) is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development. Development 134: 167-176.
60. Lin H, Spradling AC. 1997. A novel group of pumilio mutations affects the asymmetric division of germline stem cells in the Drosophila ovary. Development 124: 2463-2476.
61. Lopez de Silanes I, Fan J, Yang X, Zonderman AB, Potapova O, Pizer ES, Gorospe M. 2003. Role of the RNA-binding protein HuR in colon carcinogenesis. Oncogene 22: 7146-7154.
62. Lunghi P, Tabilio A, Dall'Aglio PP, Ridolo E, Carlo-Stella C, Pelicci PG, Bonati A. 2003. Downmodulation of ERK activity inhibits the proliferation and induces the apoptosis of primary acute myelogenous leukemia blasts. Leukemia 17: 1783-1793.
63. Malemud CJ. 2007. Inhibitors of stress-activated protein/mitogen-activated protein kinase pathways. Curr Opin Pharmacol 7: 339-343.
64. Marchetti S, Gimond C, Chambard JC, Touboul T, Roux D, Pouyssegur J, Pages G. 2005. Extracellular signal-regulated kinases phosphorylate mitogen-activated protein kinase phosphatase 3/DUSP6 at serines 159 and 97, two sites critical for its proteasomal degradation. Mol Cell Biol 25: 854-864.
65. Marshall CJ, Leevers SJ. 1995. Mitogen-activated protein kinase activation by scrape loading of p21ras. Methods Enzymol 255: 273-279.
66. Marshall MS. 1995. Ras target proteins in eukaryotic cells. FASEB J 9: 1311-1318.
67. Milella M, Kornblau SM, Estrov Z, Carter BZ, Lapillonne H, Harris D, Konopleva M, Zhao S, Estey E, Andreeff M. 2001. Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia. J Clin Invest 108: 851-859.
68. Moore FL, Jaruzelska J, Fox MS, Urano J, Firpo MT, Turek PJ, Dorfman DM, Pera RA. 2003. Human Pumilio-2 is expressed in embryonic stem cells and germ cells and interacts with DAZ (Deleted in AZoospermia) and DAZ-like proteins. Proc Natl Acad Sci USA 100: 538-543.
69. Morgan CT, Lee MH, Kimble J. 2010. Chemical reprogramming of Caenorhabditis elegans germ cell fate. Nat Chem Biol 6: 102-104.
70. Morgan MA, Dolp O, Reuter CW. 2001. Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling. Blood 97: 1823-1834.
71. Morris AR, Mukherjee N, Keene JD. 2008. Ribonomic analysis of human Pum1 reveals cis-trans conservation across species despite evolution of diverse mRNA target sets. Mol Cell Biol 28: 4093-4103.
72. Nykamp K, Lee MH, Kimble J. 2008. C. elegans La-related protein, LARP-1, localizes to germline P bodies and attenuates Ras-MAPK signaling during oogenesis. RNA 14: 1378-1389.
73. Oh JS, Kim JJ, Byun JY, Kim IA. 2010. Lin28-let7 modulates radiosensitivity of human cancer cells with activation of K-Ras. Int J Radiat Oncol Biol Phys 76: 5-8.
74. Ohkuni K, Kikuchi Y, Hara K, Taneda T, Hayashi N, Kikuchi A. 2006. Suppressor analysis of the mpt5/htr1/uth4/puf5 deletion in Saccharomyces cerevisiae. Mol Genet Genomics 275: 81-88.
75. Ohshima K, Inoue K, Fujiwara A, Hatakeyama K, Kanto K, Watanabe Y, Muramatsu K, Fukuda Y, Ogura S, Yamaguchi K, Mochizuki T. 2010. Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. PLoS One 5: e13247.
76. Owens DM, Keyse SM. 2007. Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene 26: 3203-3213.
77. Pasquinelli AE, Ruvkun G. 2002. Control of developmental timing by micrornas and their targets. Annu Rev Cell Dev Biol 18: 495-513.
78. Peng SS, Chen CY, Xu N, Shyu AB. 1998. RNA stabilization by the AU-rich element binding protein, HuR, an ELAV protein. EMBO J 17: 3461-3470.
79. Prinz S, Aldridge C, Ramsey SA, Taylor RJ, Galitski T. 2007. Control of signaling in a MAP-kinase pathway by an RNA-binding protein. PLoS One 2: e249.
80. Ricarte-Filho JC, Fuziwara CS, Yamashita AS, Rezende E, da-Silva MJ, Kimura ET. 2009. Effects of let-7 microRNA on Cell Growth and Differentiation of Papillary Thyroid Cancer. Transl Oncol 2: 236-241.
81. Schumacher B, Hanazawa M, Lee MH, Nayak S, Volkmann K, Hofmann ER, Hengartner M, Schedl T, Gartner A. 2005. Translational repression of C. elegans p53 by GLD-1 regulates DNA damage-induced apoptosis. Cell 120: 357-368.
82. Sengupta A, Cancelas JA. 2010. Cancer stem cells: A stride towards cancer cure? J Cell Physiol 225: 7-14.
83. Siomi H, Choi M, Siomi MC, Nussbaum RL, Dreyfuss G. 1994. Essential role for KH domains in RNA binding: Impaired RNA binding by a mutation in the KH domain of FMR1 that causes fragile X syndrome. Cell 77: 33-39.
84. Siomi H, Matunis MJ, Michael WM, Dreyfuss G. 1993. The pre-mRNA binding K protein contains a novel evolutionarily conserved motif. Nucleic Acids Res 21: 1193-1198.
85. Smith TG, Sweetman D, Patterson M, Keyse SM, Munsterberg A. 2005. Feedback interactions between MKP3 and ERK MAP kinase control scleraxis expression and the specification of rib progenitors in the developing chick somite. Development 132: 1305-1314.
86. Spassov DS, Jurecic R. 2003. The PUF family of RNA-binding proteins: does evolutionarily conserved structure equal conserved function? IUBMB Life 55: 359-366.
87. Stewart MS, Krause SA, McGhie J, Gray JV. 2007. Mpt5p, a stress tolerance- and lifespan-promoting PUF protein in Saccharomyces cerevisiae, acts upstream of the cell wall integrity pathway. Eukaryot Cell 6: 262-270.
88. Sugiura R, Kita A, Shimizu Y, Shuntoh H, Sio SO, Kuno T. 2003. Feedback regulation of MAPK signalling by an RNA-binding protein. Nature 424: 961-965.
89. Sugiura R, Toda T, Shuntoh H, Yanagida M, Kuno T. 1998. pmp1+, a suppressor of calcineurin deficiency, encodes a novel MAP kinase phosphatase in fission yeast. EMBO J 17: 140-148.
90. Tadauchi T, Matsumoto K, Herskowitz I, Irie K. 2001. Post-transcriptional regulation through the HO 3'-UTR by Mpt5, a yeast homolog of Pumilio and FBF. EMBO J 20: 552-561.
91. Thompson BE, Bernstein DS, Bachorik JL, Petcherski AG, Wickens M, Kimble J. 2005. A FOG-1/CPEB gradient controls the C-elegans germ line. Dev Biol 283: 584-584.
92. Valverde R, Edwards L, Regan L. 2008. Structure and function of KH domains. FEBS J 275: 2712-2726.
93. Wang J, Wang B, Bi J, Zhang C. 2010a. Cytoplasmic HuR expression correlates with angiogenesis, lymphangiogenesis, and poor outcome in lung cancer. Med Oncol [E-pub ahead of print] DOI: 10.1007/s12032-010-9734-6.
94. Wang PY, Rao JN, Zou T, Liu L, Xiao L, Yu TX, Turner DJ, Gorospe M, Wang JY. 2010b. Post-transcriptional regulation of MEK-1 by polyamines through the RNA-binding protein HuR modulating intestinal epithelial apoptosis. Biochem J 426: 293-306.
95. White EK, Moore-Jarrett T, Ruley HE. 2001. PUM2, a novel murine puf protein, and its consensus RNA-binding site. RNA 7: 1855-1866.
96. Wickens M, Bernstein D, Crittenden S, Luitjens C, Kimble J. 2001. PUF proteins and 3′UTR regulation in the Caenorhabditis elegans germ line. Cold Spring Harbor Symp Quant Biol 337-343
97. Wickens M, Bernstein DS, Kimble J, Parker R. 2002. A PUF family portrait: 3'UTR regulation as a way of life. Trends Genet 18: 150-157.
98. Wolin SL, Cedervall T. 2002. The La protein. Annu Rev Biochem 71: 375-403.
99. Xu BE, Skowronek KR, Kurjan J. 2001. The N terminus of Saccharomyces cerevisiae Sst2p plays an RGS-domain-independent, Mpt5p-dependent role in recovery from pheromone arrest. Genetics 159: 1559-1571.
100. Xu EY, Chang R, Salmon NA, Reijo Pera RA. 2007. A gene trap mutation of a murine homolog of the Drosophila stem cell factor Pumilio results in smaller testes but does not affect litter size or fertility. Mol Reprod Dev 74: 912-921.
101. Zanin E, Pacquelet A, Scheckel C, Ciosk R, Gotta M. 2010. LARP-1 promotes oogenesis by repressing fem-3 in the C. elegans germline. J Cell Sci 123: 2717-2724.
102. Zhang BL, Gallegos M, Puoti A, Durkin E, Fields S, Kimble J, Wickens MP. 1997. A conserved RNA-binding protein that regulates sexual fates in the C-elegans hermaphrodite germ line. Nature 390: 477-484.