Ribosomal Protein L11 Negatively Regulates Oncoprotein MDM2 and Mediates a p53-Dependent Ribosomal-Stress Checkpoint Pathway

Abstract

The gene encoding p53 mediates a major tumor suppression pathway that is frequently altered in human cancers. p53 function is kept at a low level during normal cell growth and is activated in response to various cellular stresses. The MDM2 oncoprotein plays a key role in negatively regulating p53 activity by either direct repression of p53 transactivation activity in the nucleus or promotion of p53 degradation in the cytoplasm. DNA damage and oncogenic insults, the two best-characterized p53-dependent checkpoint pathways, both activate p53 through inhibition of MDM2. Here we report that the human homologue of MDM2, HDM2, binds to ribosomal protein L11. L11 binds a central region in HDM2 that is distinct from the ARF binding site. We show that the functional consequence of L11-HDM2 association, like that with ARF, results in the prevention of HDM2-mediated p53 ubiquitination and degradation, subsequently restoring p53-mediated transactivation, accumulating p21 protein levels, and inducing a p53-dependent cell cycle arrest by canceling the inhibitory function of HDM2. Interference with ribosomal biogenesis by a low concentration of actinomycin D is associated with an increased L11-HDM2 interaction and subsequent p53 stabilization. We suggest that L11 functions as a negative regulator of HDM2 and that there might exist in vivo an L11-HDM2-p53 pathway for monitoring ribosomal integrity.

Translational research? Ribosome integrity and a new p53 tumor suppressor checkpoint

“…An alternative, but not mutually exclusive, mechanism for p53 sensing the integrity of the translation process centers on the binding of Mdm2 to the ribosomal proteins L5, L11 and L23. [23][24][25][26][27] It is therefore tempting to speculate that upon translational stress that L5, L11 and/or L23 become accessible to negatively feedback upon Mdm2 and activate p53 (Figure 1). Likewise, p53 is covalently associated with 5.8S RNA, 28 which interacts with L5 and 5S RNA, both of which bind Mdm2.…”

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

“…Nearly a decade later, in screens seeking out novel Mdm2 modulating proteins, the large subunit RPs RPL5, RPL11 and RPL23 were all reported to bind to Mdm2, block the E3 ubiquitin ligase function of Mdm2, and promote p53 accumulation (Lohrum et al, 2003;Zhang et al, 2003;Bhat et al, 2004;Jin et al, 2004). Following these initial reports, additional evidence subsequently was produced to support the roles of RPS7 (Chen et al, 2007;Zhu et al, 2009), RPL26 (Ofir-Rosenfeld et al, 2008 and RPS3 (Yadavilli et al, 2009) as Mdm2-binding partners.…”

The balance between rRNA and ribosomal protein synthesis up- and downregulates the tumour suppressor p53 in mammalian cells

“…In fact, the large subunit ribosome proteins rpL5, rpL11 and rpL23 were all reported to bind MDM2, thus inducing p53 stabilisation by inhibiting its E3 ubiquitin ligase function (Lohrum et al, 2003;Zhang et al, 2003;Bhat et al, 2004;Jin et al, 2004). The impairment of the nucleolar function has been proposed as a common denominator of many signalling pathways leading both to the suppression of MDM2 function and to p53 stabilisation and activation (Rubbi and Milner, 2003).…”