Abstract
Inactivation of tumor suppressors is among the rate-limiting steps in carcinogenesis that occur during the tumor promotion stage. The translation inhibitor programmed cell death 4 (Pdcd4) suppresses tumorigenesis and invasion. Although Pdcd4 is not mutationally inactivated in human cancer, the mechanisms controlling Pdcd4 inactivation during tumorigenesis remain elusive. We report that tumor promoter 12-O-tetradecanoylphorbol-13-acetate exposure decreases protein levels of Pdcd4 in mouse skin papillomas and keratinocytes as well as in human HEK293 cells. This decrease is attributable to increased proteasomal degradation of Pdcd4 and is mediated by protein kinase C-dependent activation of phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin-p70(S6K) and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK signaling. Both Akt and p70(S6K) phosphorylate Pdcd4, allowing for binding of the E3-ubiquitin ligase beta-TrCP and consequently ubiquitylation. MEK-ERK signaling on the other hand facilitates the subsequent proteasomal degradation. We further show that Pdcd4 protein levels in vivo are limiting for tumor formation, establishing Pdcd4 as a haploinsufficient tumor suppressor in Pdcd4-deficient mice. Thus, because endogenous Pdcd4 levels are limiting for tumorigenesis, inhibiting signaling to Pdcd4 degradation may prove a valid strategy for cancer prevention and intervention.
Highlights
programmed cell death 4 (Pdcd4) is a novel suppressor of tumorigenesis, tumor progression, and invasion that acts following initiator/promoter challenge or without challenge [1,2,3]
The papillomas that formed showed a substantial decrease in Pdcd4 protein levels irrespective of the initial Pdcd4 status [2]
In HEK293 cells, TPA decreased Pdcd4 protein levels in a concentration-dependent manner (Fig. 1B) and in a timedependent manner (Fig. 1C). Both phosphatidylinositol 3-kinase (PI3K) and MEK signaling pathways, as measured by GSK3h and extracellular signal-regulated kinase (ERK) phosphorylation status, respectively, were induced by TPA starting at 10 minutes
Summary
Pdcd is a novel suppressor of tumorigenesis, tumor progression, and invasion that acts following initiator/promoter challenge or without challenge [1,2,3]. A number of tumor suppressors target transcription, Pdcd is the first suppressor found to target translation. Translational dysregulation has been increasingly acknowledged as contributing to carcinogenesis. Inactivation of tumor suppressors contributes to oncogenesis. Most tumor suppressors, including p53, are mutationally inactivated, others such as p27 and Pdcd are not [11, 12]. Pdcd expression is down-regulated with progression in a number of human cancer sites such as lung and colon [13,14,15]. Just how Pdcd is inactivated during carcinogenesis is unknown
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