Racing to block tumorigenesis after pRb loss: An innocuous point mutation wins with synthetic lethality

Frederick Bauzon, Liang Zhu

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

A major goal of tumor suppressor research is to neutralize the tumorigenic effects of their loss. Since loss of pRb does not induce tumorigenesis in many types of cells, natural mechanisms may neutralize the tumorigenic effects of prb loss in these cells. For susceptible cells, neutralizing the tumorigenic effects of pRb loss could logically be achieved by correcting the deregulated activities of pRb targets to render pRb-deficient cells less abnormal. This line of research has unexpectedly revealed that knocking out the prb target Skp2 did not render Rb1 deficient cells less abnormal but, rather, induced apoptosis in them, thereby completely blocking tumorigenesis in Rb1+/- mice and after targeted deletion of Rb1 in pituitary intermediate lobe (IL). Skp2 is a substrate-recruiting component of the SCFSkp2 E3 biquitin ligase; one of its substrates is Thr187-phosphorylated p27Kip1. A p27T187A knockin (KI) mutation phenocopied Skp2 knockout (KO) in inducing apoptosis following Rb1 loss. Thus, Skp2 KO or p27T187A KI are synthetic lethal with pRb inactivation. Since homozygous p27T187A KI mutations show no adverse effects in mice, inhibiting p27T187 phosphorylation or p27T187p ubiquitination could be a highly therapeutic and minimally toxic intervention strategy for pRb deficiency-induced tumorigenesis.

Original languageEnglish (US)
Pages (from-to)2118-2123
Number of pages6
JournalCell Cycle
Volume9
Issue number11
DOIs
StatePublished - Jun 1 2010

Fingerprint

Point Mutation
Carcinogenesis
Intermediate Pituitary Gland
Apoptosis
Mutation
Ubiquitin-Protein Ligases
Poisons
Ubiquitination
Research
Phosphorylation
Synthetic Lethal Mutations
Neoplasms
Therapeutics

Keywords

  • E2F
  • p27
  • pRb
  • Skp2
  • Synthetic lethal

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

Racing to block tumorigenesis after pRb loss : An innocuous point mutation wins with synthetic lethality. / Bauzon, Frederick; Zhu, Liang.

In: Cell Cycle, Vol. 9, No. 11, 01.06.2010, p. 2118-2123.

Research output: Contribution to journalArticle

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