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PMID: 9819431 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Strain-dependent myeloid hyperplasia, growth deficiency, and accelerated cell cycle in mice lacking the Rb-related p107 gene.

Molecular and cellular biology ·Vol. 18 ·No. 12 ·1998-12-00 ·Pages 7455-65

LeCouter JE, Kablar B, Hardy WR, Ying C, Megeney LA, May LL, Rudnicki MA

Abstract

To investigate the function of the Rb-related p107 gene, a null mutation in p107 was introduced into the germ line of mice and bred into a BALB/cJ genetic background. Mice lacking p107 were viable and fertile but displayed impaired growth, reaching about 50% of normal weight by 21 days of age. Mutant mice exhibited a diathetic myeloproliferative disorder characterized by ectopic myeloid hyperplasia in the spleen and liver. Embryonic p107(-/-) fibroblasts and primary myoblasts isolated from adult p107(-/-) mice displayed a striking twofold acceleration in doubling time. However, cell sort analysis indicated that the fraction of cells in G1, S, and G2 was unaltered, suggesting that the different phases of the cell cycle in p107(-/-) cells was uniformly reduced by a factor of 2. Western analysis of cyclin expression in synchronized p107(-/-) fibroblasts revealed that expression of cyclins E and A preceded that of D1. Mutant embryos expressed approximately twice the normal level of Rb, whereas p130 levels were unaltered. Lastly, mutant mice reverted to a wild-type phenotype following a single backcross with C57BL/6J mice, suggesting the existence of modifier genes that have potentially epistatic relationships with p107. Therefore, we conclude that p107 is an important player in negatively regulating the rate of progression of the cell cycle, but in a strain-dependent manner.

MeSH Terms
Animals Cell Cycle/genetics Cells, Cultured Crosses, Genetic Cyclins/metabolism Flow Cytometry Growth Disorders/genetics Histocytochemistry Immunohistochemistry Kinetics Liver/pathology Lymphoproliferative Disorders/genetics Mice Mice, Knockout Nuclear Proteins/genetics Phenotype RNA, Messenger/genetics Retinoblastoma-Like Protein p107 Spleen/pathology
Chemicals
Cyclins Nuclear Proteins RNA, Messenger Rbl1 protein, mouse Retinoblastoma-Like Protein p107
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
LeCouter J E
Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario, Canada L8S 4K1.
Kablar B
Hardy W R
Ying C
Megeney L A
May L L
Rudnicki M A
References (63)
63 references, click to expand
  1. p27KIP1 blocks cyclin E-dependent transactivation of cyclin A gene expression.
    Mol Cell Biol. 1997 Jan;17(1):407-15 PMID: 8972221
  2. Targeted disruption of the mouse beta1-adrenergic receptor gene: developmental and cardiovascular effects.
    Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7375-80 PMID: 8693001
  3. pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes.
    Genes Dev. 1997 Jun 1;11(11):1447-63 PMID: 9192872
  4. Role of the Rb/E2F pathway in cell growth control.
    J Cell Physiol. 1997 Nov;173(2):233-6 PMID: 9365528
  5. E2F transcription factor action, regulation and possible role in human cancer.
    Cell Prolif. 1997 Mar-Apr;30(3-4):97-105 PMID: 9375022
  6. MyoD and Myf-5 differentially regulate the development of limb versus trunk skeletal muscle.
    Development. 1997 Dec;124(23):4729-38 PMID: 9428409
  7. Retinoblastoma protein recruits histone deacetylase to repress transcription.
    Nature. 1998 Feb 5;391(6667):597-601 PMID: 9468139
  8. Retinoblastoma protein represses transcription by recruiting a histone deacetylase.
    Nature. 1998 Feb 5;391(6667):601-5 PMID: 9468140
  9. Rb interacts with histone deacetylase to repress transcription.
    Cell. 1998 Feb 20;92(4):463-73 PMID: 9491888
  10. The retinoblastoma gene family: cousins with overlapping interests.
    Trends Genet. 1998 Jun;14(6):223-9 PMID: 9635405
  11. Strain-dependent embryonic lethality in mice lacking the retinoblastoma-related p130 gene.
    Development. 1998 Dec;125(23):4669-79 PMID: 9806916
  12. The retinoblastoma protein and cell cycle control.
    Cell. 1995 May 5;81(3):323-30 PMID: 7736585
  13. Direct transcriptional repression by pRB and its reversal by specific cyclins.
    Mol Cell Biol. 1995 Jun;15(6):3256-65 PMID: 7760821
  14. Transcriptional regulation during the mammalian cell cycle.
    Trends Genet. 1995 May;11(5):173-8 PMID: 7785076
  15. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype.
    Science. 1995 Jul 14;269(5221):230-4 PMID: 7618084
  16. Strain-dependent epithelial defects in mice lacking the EGF receptor.
    Science. 1995 Jul 14;269(5221):234-8 PMID: 7618085
  17. A link between increased transforming activity of lymphoma-derived MYC mutant alleles, their defective regulation by p107, and altered phosphorylation of the c-Myc transactivation domain.
    Mol Cell Biol. 1995 Aug;15(8):4031-42 PMID: 7623799
  18. Cellular targets for activation by the E2F1 transcription factor include DNA synthesis- and G1/S-regulatory genes.
    Mol Cell Biol. 1995 Aug;15(8):4215-24 PMID: 7623816
  19. The retinoblastoma protein and its relatives.
    Semin Cancer Biol. 1995 Apr;6(2):83-90 PMID: 7647310
  20. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development.
    Genes Dev. 1995 Oct 1;9(19):2364-72 PMID: 7557388
  21. Developmental expression of p107 mRNA and evidence for alternative splicing of the p107 (RBL1) gene product.
    Genomics. 1995 Aug 10;28(3):520-9 PMID: 7490090
  22. Characterization of cis-regulatory elements of the c-myc promoter responding to human GM-CSF or mouse interleukin 3 in mouse proB cell line BA/F3 cells expressing the human GM-CSF receptor.
    Mol Biol Cell. 1995 Jun;6(6):627-36 PMID: 7579683
  23. Cell cycle regulation of the cyclin A gene promoter is mediated by a variant E2F site.
    Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11264-8 PMID: 7479977
  24. Transforming growth factor-beta 3 is required for secondary palate fusion.
    Nat Genet. 1995 Dec;11(4):409-14 PMID: 7493021
  25. Role of E2F in cell cycle control and cancer.
    Front Biosci. 1998 Apr 27;3:d447-8 PMID: 9556498
  26. Deletion of the long arm of chromosome 20 [del(20)(q11)] in myeloid disorders.
    Blood. 1978 Nov;52(5):868-77 PMID: 698393
  27. The E2F transcription factor is a cellular target for the RB protein.
    Cell. 1991 Jun 14;65(6):1053-61 PMID: 1828392
  28. The mouse Pgk-1 gene promoter contains an upstream activator sequence.
    Nucleic Acids Res. 1991 Oct 25;19(20):5755-61 PMID: 1945853
  29. Independent binding of the retinoblastoma protein and p107 to the transcription factor E2F.
    Nature. 1992 Jan 9;355(6356):176-9 PMID: 1530885
  30. The transcription factor E2F interacts with the retinoblastoma product and a p107-cyclin A complex in a cell cycle-regulated manner.
    Cell. 1992 Jan 10;68(1):157-66 PMID: 1531040
  31. The interaction of RB with E2F coincides with an inhibition of the transcriptional activity of E2F.
    Genes Dev. 1992 Feb;6(2):177-85 PMID: 1531329
  32. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality.
    Cell. 1992 Jun 12;69(6):915-26 PMID: 1606615
  33. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis.
    Nature. 1992 Sep 24;359(6393):288-94 PMID: 1406932
  34. Effects of an Rb mutation in the mouse.
    Nature. 1992 Sep 24;359(6393):295-300 PMID: 1406933
  35. Requirement for a functional Rb-1 gene in murine development.
    Nature. 1992 Sep 24;359(6393):328-30 PMID: 1406937
  36. Inactivation of MyoD in mice leads to up-regulation of the myogenic HLH gene Myf-5 and results in apparently normal muscle development.
    Cell. 1992 Oct 30;71(3):383-90 PMID: 1330322
  37. Cell cycle analysis of E2F in primary human T cells reveals novel E2F complexes and biochemically distinct forms of free E2F.
    Mol Cell Biol. 1993 Jul;13(7):3975-83 PMID: 8321204
  38. Expression of a retinoblastoma transgene results in dwarf mice.
    Genes Dev. 1993 Sep;7(9):1654-62 PMID: 8370518
  39. Expression of transcription factor E2F1 induces quiescent cells to enter S phase.
    Nature. 1993 Sep 23;365(6444):349-52 PMID: 8377827
  40. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r).
    Cell. 1993 Oct 8;75(1):59-72 PMID: 8402901
  41. Role of insulin-like growth factors in embryonic and postnatal growth.
    Cell. 1993 Oct 8;75(1):73-82 PMID: 8402902
  42. Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin.
    Development. 1993 Dec;119(4):1079-91 PMID: 8306876
  43. Binding and suppression of the Myc transcriptional activation domain by p107.
    Science. 1994 Apr 8;264(5156):251-4 PMID: 8146655
  44. An E2F binding sequence negatively regulates the response of the insulin-like growth factor 1 (IGF-I) promoter to simian virus 40T antigen and to serum.
    Oncogene. 1994 Aug;9(8):2125-34 PMID: 8035997
  45. Interaction of c-Myc with the pRb-related protein p107 results in inhibition of c-Myc-mediated transactivation.
    EMBO J. 1994 Sep 1;13(17):4080-6 PMID: 8076603
  46. Molecular analysis of chromosome 20q deletions associated with myeloproliferative disorders and myelodysplastic syndromes.
    Blood. 1994 Nov 1;84(9):3086-94 PMID: 7949181
  47. Cooperative tumorigenic effects of germline mutations in Rb and p53.
    Nat Genet. 1994 Aug;7(4):480-4 PMID: 7951317
  48. Deregulated expression of E2F-1 induces S-phase entry and leads to apoptosis.
    Mol Cell Biol. 1994 Dec;14(12):8166-73 PMID: 7969153
  49. The transcription factor E2F-1 is a downstream target of RB action.
    Mol Cell Biol. 1995 Feb;15(2):742-55 PMID: 7823942
  50. A potent transrepression domain in the retinoblastoma protein induces a cell cycle arrest when bound to E2F sites.
    Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11544-8 PMID: 8524800
  51. Regulation of the cyclin E gene by transcription factor E2F1.
    Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12146-50 PMID: 8618861
  52. Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor.
    Nat Genet. 1996 Mar;12(3):280-7 PMID: 8589719
  53. Deregulated expression of E2F family members induces S-phase entry and overcomes p16INK4A-mediated growth suppression.
    Mol Cell Biol. 1996 Mar;16(3):1047-57 PMID: 8622649
  54. Altered cell cycle kinetics, gene expression, and G1 restriction point regulation in Rb-deficient fibroblasts.
    Mol Cell Biol. 1996 May;16(5):2402-7 PMID: 8628308
  55. Cloning and expression of the Rb-related mouse p130 mRNA.
    Oncogene. 1996 Apr 4;12(7):1433-40 PMID: 8622859
  56. Transforming growth factor-beta1 modulates p107 function in myeloid cells: correlation with cell cycle progression.
    J Biol Chem. 1996 Mar 29;271(13):7811-9 PMID: 8631825
  57. MyoD is required for myogenic stem cell function in adult skeletal muscle.
    Genes Dev. 1996 May 15;10(10):1173-83 PMID: 8675005
  58. Regulation of cyclin E transcription by E2Fs and retinoblastoma protein.
    Oncogene. 1996 Mar 21;12(6):1173-80 PMID: 8649818
  59. Cell cycle regulation of the murine cyclin E gene depends on an E2F binding site in the promoter.
    Mol Cell Biol. 1996 Jul;16(7):3401-9 PMID: 8668155
  60. Cyclin A expression is under negative transcriptional control during the cell cycle.
    Mol Cell Biol. 1996 Jul;16(7):3789-98 PMID: 8668196
  61. Targeted disruption of p107: functional overlap between p107 and Rb.
    Genes Dev. 1996 Jul 1;10(13):1621-32 PMID: 8682293
  62. Shared role of the pRB-related p130 and p107 proteins in limb development.
    Genes Dev. 1996 Jul 1;10(13):1633-44 PMID: 8682294
  63. Mapping of a major genetic modifier of embryonic lethality in TGF beta 1 knockout mice.
    Nat Genet. 1997 Feb;15(2):207-11 PMID: 9020852
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.18.12.7455
Published
1998-12-00
Pages
7455-65
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC109326
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.18.12.7455 PMC Full Text View journal details
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