Tuberous Sclerosis Complex 1 Regulates dE2F1 Expression during Development and Cooperates with RBF1 to Control Proliferation and Survival

English version České info

Previous studies in Drosophila melanogaster have demonstrated that many tumor suppressor pathways impinge on Rb/E2F to regulate proliferation and survival. Here, we report that Tuberous Sclerosis Complex 1 (TSC1), a well-established tumor suppressor that regulates cell size, is an important regulator of dE2F1 during development. In eye imaginal discs, the loss of tsc1 cooperates with rbf1 mutations to promote ectopic S-phase and cell death. This cooperative effect between tsc1 and rbf1 mutations can be explained, at least in part, by the observation that TSC1 post-transcriptionally regulates dE2F1 expression. Clonal analysis revealed that the protein level of dE2F1 is increased in tsc1 or tsc2 mutant cells and conversely decreased in rheb or dTor mutant cells. Interestingly, while s6k mutations have no effect on dE2F1 expression in the wild-type background, S6k is absolutely required for the increase of dE2F1 expression in tsc2 mutant cells. The canonical TSC/Rheb/Tor/S6k pathway is also an important determinant of dE2F1-dependent cell death, since rheb or s6k mutations suppress the developmentally regulated cell death observed in rbf1 mutant eye discs. Our results provide evidence to suggest that dE2F1 is an important cell cycle regulator that translates the growth-promoting signal downstream of the TSC/Rheb/Tor/S6k pathway.

Vyšlo v časopise: Tuberous Sclerosis Complex 1 Regulates dE2F1 Expression during Development and Cooperates with RBF1 to Control Proliferation and Survival. PLoS Genet 6(8): e32767. doi:10.1371/journal.pgen.1001071
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001071

Souhrn

Zdroje

1. DysonN

1998 The regulation of E2F by pRB-family proteins. Genes Dev 12 2245 2262

2. PolagerS

GinsbergD

2008 E2F - at the crossroads of life and death. Trends Cell Biol 18 528 535

3. van den HeuvelS

DysonNJ

2008 Conserved functions of the pRB and E2F families. Nat Rev Mol Cell Biol 9 713 724

4. MullerH

BrackenAP

VernellR

MoroniMC

ChristiansF

2001 E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev 15 267 285

5. DimovaDK

StevauxO

FrolovMV

DysonNJ

2003 Cell cycle-dependent and cell cycle- independent control of transcription by the Drosophila E2F/RB pathway. Genes Dev 17 2308 2320

6. IshidaS

HuangE

ZuzanH

SpangR

LeoneG

2001 Role for E2F in control of both DNA replication and mitotic functions as revealed from DNA microarray analysis. Mol Cell Biol 21 4684 4699

7. JacksT

FazeliA

SchmittEM

BronsonRT

GoodellMA

1992 Effects of an Rb mutation in the mouse. Nature 359 295 300

8. ClarkeAR

MaandagER

van RoonM

van der LugtNM

van der ValkM

1992 Requirement for a functional Rb-1 gene in murine development. Nature 359 328 330

9. LeeEY

ChangCY

HuN

WangYC

LaiCC

1992 Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359 288 294

10. TsaiKY

HuY

MacleodKF

CrowleyD

YamasakiL

1998 Mutation of E2f-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb- deficient mouse embryos. Mol Cell 2 293 304

11. ZieboldU

RezaT

CaronA

LeesJA

2001 E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos. Genes Dev 15 386 391

12. SherrCJ

1996 Cancer cell cycles. Science 274 1672 1677

13. HarrisonDJ

HooperML

ArmstrongJF

ClarkeAR

1995 Effects of heterozygosity for the Rb-1t19neo allele in the mouse. Oncogene 10 1615 1620

14. HuN

GutsmannA

HerbertDC

BradleyA

LeeWH

1994 Heterozygous Rb-1 delta 20/+mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance. Oncogene 9 1021 1027

15. DuW

DysonN

1999 The role of RBF in the introduction of G1 regulation during Drosophila embryogenesis. EMBO J 18 916 925

16. DuronioRJ

O'FarrellPH

XieJE

BrookA

DysonN

1995 The transcription factor E2F is required for S phase during Drosophila embryogenesis. Genes Dev 9 1445 1455

17. MacPhersonD

SageJ

KimT

HoD

McLaughlinME

2004 Cell type-specific effects of Rb deletion in the murine retina. Genes Dev 18 1681 1694

18. Robanus-MaandagE

DekkerM

van der ValkM

CarrozzaML

JeannyJC

1998 p107 is a suppressor of retinoblastoma development in pRb-deficient mice. Genes Dev 12 1599 1609

19. ChenD

Livne-barI

VanderluitJL

SlackRS

AgochiyaM

2004 Cell-specific effects of RB or RB/p107 loss on retinal development implicate an intrinsically death- resistant cell-of-origin in retinoblastoma. Cancer Cell 5 539 551

20. ZhangJ

SchweersB

DyerMA

2004 The first knockout mouse model of retinoblastoma. Cell Cycle 3 952 959

21. YamasakiL

BronsonR

WilliamsBO

DysonNJ

HarlowE

1998 Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1(+/−)mice. Nat Genet 18 360 364

22. ZieboldU

LeeEY

BronsonRT

LeesJA

2003 E2F3 loss has opposing effects on different pRB-deficient tumors, resulting in suppression of pituitary tumors but metastasis of medullary thyroid carcinomas. Mol Cell Biol 23 6542 6552

23. ChenHZ

TsaiSY

LeoneG

2009 Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat Rev Cancer 9 785 797

24. StevauxO

DysonNJ

2002 A revised picture of the E2F transcriptional network and RB function. Curr Opin Cell Biol 14 684 691

25. TsaiSY

OpavskyR

SharmaN

WuL

NaiduS

2008 Mouse development with a single E2F activator. Nature 454 1137 1141

26. DuW

2000 Suppression of the rbf null mutants by a de2f1 allele that lacks transactivation domain. Development 127 367 379

27. NicolayBN

FrolovMV

2008 Context-dependent requirement for dE2F during oncogenic proliferation. PLoS Genet 4 e1000205 doi:10.1371/journal.pgen.1000205

28. NicholsonSC

GilbertMM

NicolayBN

FrolovMV

MobergKH

2009 The archipelago tumor suppressor gene limits rb/e2f-regulated apoptosis in developing Drosophila tissues. Curr Biol 19 1503 1510

29. MoonNS

Di StefanoL

DysonN

2006 A gradient of epidermal growth factor receptor signaling determines the sensitivity of rbf1 mutant cells to E2F-dependent apoptosis. Mol Cell Biol 26 7601 7615

30. MoonNS

Di StefanoL

MorrisEJ

PatelR

WhiteK

2008 E2F and p53 induce apoptosis independently during Drosophila development but intersect in the context of DNA damage. PLoS Genet 4 e1000153 doi:10.1371/journal.pgen.1000153

31. InokiK

CorradettiMN

GuanKL

2005 Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 37 19 24

32. PanD

DongJ

ZhangY

GaoX

2004 Tuberous sclerosis complex: from Drosophila to human disease. Trends Cell Biol 14 78 85

33. HarveyKF

MattilaJ

SoferA

BennettFC

RamseyMR

2008 FOXO-regulated transcription restricts overgrowth of Tsc mutant organs. J Cell Biol 180 691 696

34. FrolovMV

MoonNS

DysonNJ

2005 dDP is needed for normal cell proliferation. Mol Cell Biol 25 3027 3039

35. Tanaka-MatakatsuM

XuJ

ChengL

DuW

2009 Regulation of apoptosis of rbf mutant cells during Drosophila development. Dev Biol 326 347 356

36. GaoX

PanD

2001 TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev 15 1383 1392

37. PotterCJ

HuangH

XuT

2001 Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 105 357 368

38. TaponN

ItoN

DicksonBJ

TreismanJE

HariharanIK

2001 The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105 345 355

39. BrittonJS

EdgarBA

1998 Environmental control of the cell cycle in Drosophila: nutrition activates mitotic and endoreplicative cells by distinct mechanisms. Development 125 2149 2158

40. NeufeldTP

de la CruzAF

JohnstonLA

EdgarBA

1998 Coordination of growth and cell division in the Drosophila wing. Cell 93 1183 1193

41. ShibutaniST

de la CruzAF

TranV

TurbyfillWJ3rd

ReisT

2008 Intrinsic negative cell cycle regulation provided by PIP box- and Cul4Cdt2-mediated destruction of E2f1 during S phase. Dev Cell 15 890 900

42. RuvinskyI

MeyuhasO

2006 Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. Trends Biochem Sci 31 342 348

43. PendeM

UmSH

MieuletV

StickerM

GossVL

2004 S6K1(−/−)/S6K2(−/−) mice exhibit perinatal lethality and rapamycin-sensitive 5'-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol 24 3112 3124

44. McNeillH

CraigGM

BatemanJM

2008 Regulation of neurogenesis and epidermal growth factor receptor signaling by the insulin receptor/target of rapamycin pathway in Drosophila. Genetics 179 843 853

45. OrlicM

SpencerCE

WangL

GallieBL

2006 Expression analysis of 6p22 genomic gain in retinoblastoma. Genes Chromosomes Cancer 45 72 82

46. OldhamS

MontagneJ

RadimerskiT

ThomasG

HafenE

2000 Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin. Genes Dev 14 2689 2694

47. TettweilerG