Cyclin D/CDK4 and Cyclin E/CDK2 Induce Distinct Cell Cycle Re-Entry Programs in Differentiated Muscle Cells
Cell proliferation and differentiation are regulated in a highly coordinated and inverse manner during development and tissue homeostasis. Terminal differentiation usually coincides with cell cycle exit and is thought to engage stable transcriptional repression of cell cycle genes. Here, we examine the robustness of the post-mitotic state, using Caenorhabditis elegans muscle cells as a model. We found that expression of a G1 Cyclin and CDK initiates cell cycle re-entry in muscle cells without interfering with the differentiated state. Cyclin D/CDK4 (CYD-1/CDK-4) expression was sufficient to induce DNA synthesis in muscle cells, in contrast to Cyclin E/CDK2 (CYE-1/CDK-2), which triggered mitotic events. Tissue-specific gene-expression profiling and single molecule FISH experiments revealed that Cyclin D and E kinases activate an extensive and overlapping set of cell cycle genes in muscle, yet failed to induce some key activators of G1/S progression. Surprisingly, CYD-1/CDK-4 also induced an additional set of genes primarily associated with growth and metabolism, which were not activated by CYE-1/CDK-2. Moreover, CYD-1/CDK-4 expression also down-regulated a large number of genes enriched for catabolic functions. These results highlight distinct functions for the two G1 Cyclin/CDK complexes and reveal a previously unknown activity of Cyclin D/CDK-4 in regulating metabolic gene expression. Furthermore, our data demonstrate that many cell cycle genes can still be transcriptionally induced in post-mitotic muscle cells, while maintenance of the post-mitotic state might depend on stable repression of a limited number of critical cell cycle regulators.
Vyšlo v časopise:
Cyclin D/CDK4 and Cyclin E/CDK2 Induce Distinct Cell Cycle Re-Entry Programs in Differentiated Muscle Cells. PLoS Genet 7(11): e32767. doi:10.1371/journal.pgen.1002362
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002362
Souhrn
Cell proliferation and differentiation are regulated in a highly coordinated and inverse manner during development and tissue homeostasis. Terminal differentiation usually coincides with cell cycle exit and is thought to engage stable transcriptional repression of cell cycle genes. Here, we examine the robustness of the post-mitotic state, using Caenorhabditis elegans muscle cells as a model. We found that expression of a G1 Cyclin and CDK initiates cell cycle re-entry in muscle cells without interfering with the differentiated state. Cyclin D/CDK4 (CYD-1/CDK-4) expression was sufficient to induce DNA synthesis in muscle cells, in contrast to Cyclin E/CDK2 (CYE-1/CDK-2), which triggered mitotic events. Tissue-specific gene-expression profiling and single molecule FISH experiments revealed that Cyclin D and E kinases activate an extensive and overlapping set of cell cycle genes in muscle, yet failed to induce some key activators of G1/S progression. Surprisingly, CYD-1/CDK-4 also induced an additional set of genes primarily associated with growth and metabolism, which were not activated by CYE-1/CDK-2. Moreover, CYD-1/CDK-4 expression also down-regulated a large number of genes enriched for catabolic functions. These results highlight distinct functions for the two G1 Cyclin/CDK complexes and reveal a previously unknown activity of Cyclin D/CDK-4 in regulating metabolic gene expression. Furthermore, our data demonstrate that many cell cycle genes can still be transcriptionally induced in post-mitotic muscle cells, while maintenance of the post-mitotic state might depend on stable repression of a limited number of critical cell cycle regulators.
Zdroje
1. van den HeuvelSDysonNJ 2008 Conserved functions of the pRB and E2F families. Nat Rev Mol Cell Biol 9 713 724
2. CobrinikD 2005 Pocket proteins and cell cycle control. Oncogene 24 2796 2809
3. JacobsJJKieboomKMarinoSDePinhoRAvan LohuizenM 1999 The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397 164 168
4. BlaisAvan OevelenCJMargueronRAcosta-AlvearDDynlachtBD 2007 Retinoblastoma tumor suppressor protein-dependent methylation of histone H3 lysine 27 is associated with irreversible cell cycle exit. J Cell Biol 179 1399 1412
5. ButtittaLAEdgarBA 2007 Mechanisms controlling cell cycle exit upon terminal differentiation. Curr Opin Cell Biol 19 697 704
6. ButtittaLAKatzaroffAJPerezCLde la CruzAEdgarBA 2007 A double-assurance mechanism controls cell cycle exit upon terminal differentiation in Drosophila. Dev Cell 12 631 643
7. SageCHuangMKarimiKGutierrezGVollrathMA 2005 Proliferation of functional hair cells in vivo in the absence of the retinoblastoma protein. Science 307 1114 1118
8. AjiokaIMartinsRABayazitovITDonovanSJohnsonDA 2007 Differentiated horizontal interneurons clonally expand to form metastatic retinoblastoma in mice. Cell 131 378 390
9. XuXLFangYLeeTCForrestDGregory-EvansC 2009 Retinoblastoma has properties of a cone precursor tumor and depends upon cone-specific MDM2 signaling. Cell 137 1018 1031
10. SulstonJEHorvitzHR 1977 Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev Biol 56 110 156
11. SulstonJESchierenbergEWhiteJGThomsonJN 1983 The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev Biol 100 64 119
12. ParkMKrauseMW 1999 Regulation of postembryonic G(1) cell cycle progression in Caenorhabditis elegans by a cyclin D/CDK-like complex. Development 126 4849 4860
13. BoxemMvan den HeuvelS 2001 lin-35 Rb and cki-1 Cip/Kip cooperate in developmental regulation of G1 progression in C. elegans. Development 128 4349 4359
14. HongYRoyRAmbrosV 1998 Developmental regulation of a cyclin-dependent kinase inhibitor controls postembryonic cell cycle progression in Caenorhabditis elegans. Development 125 3585 3597
15. LuXHorvitzHR 1998 lin-35 and lin-53, two genes that antagonize a C. elegans Ras pathway, encode proteins similar to Rb and its binding protein RbAp48. Cell 95 981 991
16. BoxemMvan den HeuvelS 2002 C. elegans class B synthetic multivulva genes act in G(1) regulation. Curr Biol 12 906 911
17. SaitoRMPerreaultAPeachBSatterleeJSvan den HeuvelS 2004 The CDC-14 phosphatase controls developmental cell-cycle arrest in C. elegans. Nat Cell Biol 6 777 783
18. BuckSHChiuDSaitoRM 2009 The cyclin-dependent kinase inhibitors, cki-1 and cki-2, act in overlapping but distinct pathways to control cell cycle quiescence during C. elegans development. Cell Cycle 8
19. WirtSEAdlerASGebalaVWeimannJMSchafferBE 2010 G1 arrest and differentiation can occur independently of Rb family function. J Cell Biol 191 809 825
20. FireAWaterstonRH 1989 Proper expression of myosin genes in transgenic nematodes. EMBO J 8 3419 3428
21. FoxRMWatsonJDVon StetinaSEMcDermottJBrodiganTM 2007 The embryonic muscle transcriptome of Caenorhabditis elegans. Genome Biol 8 R188
22. KorzeliusJTheIRuijtenbergSPortegijsVXuH 2011 C. elegans MCM-4 is a general DNA replication and checkpoint component with an epidermis-specific requirement for growth and viability. Dev Biol 350 358 369
23. SalicAMitchisonTJ 2008 A chemical method for fast and sensitive detection of DNA synthesis in vivo. Proc Natl Acad Sci U S A 105 2415 2420
24. MoermanDGWilliamsBD 2006 Sarcomere assembly in C. elegans muscle. WormBook 1 16
25. RoyPJStuartJMLundJKimSK 2002 Chromosomal clustering of muscle-expressed genes in Caenorhabditis elegans. Nature 418 975 979
26. BerrizGFKingODBryantBSanderCRothFP 2003 Characterizing gene sets with FuncAssociate. Bioinformatics 19 2502 2504
27. KirienkoNVFayDS 2007 Transcriptome profiling of the C. elegans Rb ortholog reveals diverse developmental roles. Dev Biol 305 674 684
28. DuronioRJO'FarrellPH 1995 Developmental control of the G1 to S transition in Drosophila: cyclin E is a limiting downstream target of E2F. Genes Dev 9 1456 1468
29. RajAvan den BogaardPRifkinSAvan OudenaardenATyagiS 2008 Imaging individual mRNA molecules using multiple singly labeled probes. Nat Methods 5 877 879
30. SherrCJ 2004 Principles of tumor suppression. Cell 116 235 246
31. DatarSAJacobsHWde la CruzAFLehnerCFEdgarBA 2000 The Drosophila cyclin D-Cdk4 complex promotes cellular growth. EMBO J 19 4543 4554
32. MeyerCAJacobsHWDatarSADuWEdgarBA 2000 Drosophila Cdk4 is required for normal growth and is dispensable for cell cycle progression. EMBO J 19 4533 4542
33. BienvenuFJirawatnotaiSEliasJEMeyerCAMizerackaK 2010 Transcriptional role of cyclin D1 in development revealed by a genetic-proteomic screen. Nature 463 374 378
34. Van GilstMRHadjivassiliouHJollyAYamamotoKR 2005 Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans. PLoS Biol 3 e53 doi:10.1371/journal.pbio.0030053
35. MailandNDiffleyJF 2005 CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis. Cell 122 915 926
36. KimJFengHKipreosET 2007 C. elegans CUL-4 prevents rereplication by promoting the nuclear export of CDC-6 via a CKI-1-dependent pathway. Curr Biol 17 966 972
37. KorzeliusJvan den HeuvelS 2007 Replication licensing: oops!... I did it again. Curr Biol 17 R630 632
38. ButtittaLAKatzaroffAJEdgarBA 2010 A robust cell cycle control mechanism limits E2F-induced proliferation of terminally differentiated cells in vivo. J Cell Biol 189 981 996
39. FukushigeTHawkinsMGMcGheeJD 1998 The GATA-factor elt-2 is essential for formation of the Caenorhabditis elegans intestine. Dev Biol 198 286 302
40. Frokjaer-JensenCDavisMWHollopeterGTaylorJHarrisTW Targeted gene deletions in C. elegans using transposon excision. Nat Methods 7 451 453
41. BoxemMSrinivasanDGvan den HeuvelS 1999 The Caenorhabditis elegans gene ncc-1 encodes a cdc2-related kinase required for M phase in meiotic and mitotic cell divisions, but not for S phase. Development 126 2227 2239
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 11
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