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Abstract
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.