FIGURE 3.

Regulation of hTERT levels in the nucleus and cytoplasm. (A) PLK1 facilitates hTERT localization to the nucleus. (B) In the nucleus PLK1 interferes with hTERT ubiquitination by MDM2 and UBE2D3 and subsequent degradation of hTERT by the proteasome. (C) In addition, PLK1 prevents hTERT proteasomal degradation by interfering with ubiquitination of hTERT by MKRN1. (D) hTERT binding to telomeres is prevented by TRF1, which is stabilized at telomeres by PINX1. However, PINX1 is a target of phosphorylation by PLK1, resulting in recruitment of E3 ligases that recognize phosphorylated PINX1. This promotes ubiquitination and proteasomal degradation of PINX1. (E) In the cytoplasm, the E3 ligase CHIP inhibits PLK1-facilitated transport of hTERT to the nucleus by interacting with hTERT. Subsequently, CHIP can ubiquitinate hTERT and target it for proteasomal degradation.