Rb Regulates DNA damage response and cellular senescence through E2F-dependent suppression of N-ras isoprenylation.
Oncogene-induced cellular senescence is well documented, but little is known about how infinite cell proliferation induced by loss of tumor suppressor genes is antagonized by cellular functions. Rb heterozygous mice generate Rb-deficient C cell adenomas that progress to adenocarcinomas following biallelic loss of N-ras. Here, we demonstrate that pRb inactivation induces aberrant expression of farnesyl diphosphate synthase, many prenyltransferases, and their upstream regulators sterol regulatory element-binding proteins (SREBPs) in an E2F-dependent manner, leading to enhanced isoprenylation and activation of N-Ras. Consequently, elevated N-Ras activity induces DNA damage response and p130-dependent cellular senescence in Rb-deficient cells. Furthermore, Rb heterozygous mice additionally lacking any of Ink4a, Arf, or Suv39h1 generated C cell adenocarcinomas, suggesting that cellular senescence antagonizes Rb-deficient carcinogenesis.
Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Awad
A
Shamma
Yujiro
Y
Takegami
Takao
T
Miki
Shunsuke
S
Kitajima
Makoto
M
Noda
Takao
T
Obara
Takahiro
T
Okamoto
Chiaki
C
Takahashi
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D020295:Brain Stem Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002462:Cell Membrane; D016922:Cellular Senescence; D047369:Chromatin Immunoprecipitation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D004249:DNA Damage; D004260:DNA Repair; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D018345:Mice, Knockout; D054876:Prenylation; D017368:Protein Prenylation; D021381:Protein Transport; D016160:Retinoblastoma Protein / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050684:E2F Transcription Factors; D016160:Retinoblastoma Protein