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

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.

Figure 1

Consequences of pRb loss. a. pRb functions to suppress tumorigenesis via its targets. Only E2Fs and Skp2 are listed among the more than 100 pRb targets. One function of Skp2 is to target p27T187p for ubiquitination, and this function is inhibited by pRb. b. Loss of pRb leads to deregulation of its targets (indicated by red color). Deregulation of Skp2 leads to ubiquitination and degradation of p27 (indicated by grey color). The outcome of pRb loss is tumorigenesis. c. When Skp2 is also deleted, p27 is prevented from ubiquitination and degradation. The outcome of pRb loss in this scenario becomes apoptosis. d. When p27T187 is mutated to p27T187A, p27 is also prevented from ubiquitination and degradation, and the outcome of pRb loss also becomes apoptosis.