Abstract
PTEN is a critical tumour suppressor that is frequently mutated in human cancer. We have previously identified a CUG initiated PTEN isoform designated PTENα, which functions in mitochondrial bioenergetics. Here we report the identification of another N-terminal extended PTEN isoform, designated PTENβ. PTENβ translation is initiated from an AUU codon upstream of and in-frame with the AUG initiation sequence for canonical PTEN. We show that the Kozak context and a downstream hairpin structure are critical for this alternative initiation. PTENβ localizes predominantly in the nucleolus, and physically associates with and dephosphorylates nucleolin, which is a multifunctional nucleolar phosphoprotein. Disruption of PTENβ alters rDNA transcription and promotes ribosomal biogenesis, and this effect can be reversed by re-introduction of PTENβ. Our data show that PTENβ regulates pre-rRNA synthesis and cellular proliferation. These results demonstrate the complexity of the PTEN protein family and the diversity of its functions.
Highlights
PTEN is a critical tumour suppressor that is frequently mutated in human cancer
We found that PTENa and PTENb double knockout N-terminal region important for nucleolin function (Fig. 5h). led to elevation of nucleolin phosphorylation levels at Thr[84], exogenous expression of wild-type PTENb but not which is one of the XTPXKKXX motifs located in the nucleolin protein phosphatase activity abolished PTENb efficiently a pCMV
Exogenous expression of PTENb but not PTENa in PTENa and PTENb null cells efficiently downregulated 28S and 18S rRNA levels (Fig. 6b, lane 3 versus lane 2 and Supplementary Fig. 8a). These results argue that PTENb plays a role in regulation of rRNA, and in particular is involved in regulation of pre-rRNA synthesis from the outset of ribosome biogenesis
Summary
PTEN is a critical tumour suppressor that is frequently mutated in human cancer. We have previously identified a CUG initiated PTEN isoform designated PTENa, which functions in mitochondrial bioenergetics. The translation initiation codon is generally recognized and selected by the 50cap structure dependent ribosomal scanning mechanism, as well as by 50cap structure independent internal ribosome entry sites This scanning complex rigorously controls the fidelity of initiation through recognition of the correct AUG triplet in the optimum context GCC(A/G)CCAUGG, referred to as the Kozak sequence, which includes a purine at the À 3 and a G at the þ 4 position (relative to the A of the AUG codon, which is designated þ 1) (refs 18,19). Disruption of PTENb leads to an abnormal increase in pre-rRNA synthesis and results in promotion of cellular proliferation These findings characterize an N-terminal extended PTEN isoform with distinct localization and function, which results from alternative AUU translation initiation. Identification of PTENb further reveals the diversity of PTEN protein family function, and the correspondence of protein function with isoform subtype
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