| |||
|
|
|||
|
      |
|
 |
|
| |||||||||||
| |||||||||||
| |||||||||||
| | | | ||||||||
| Pml: Thwarting Akt-driven tumorigenesis
The tumor suppressor promyelocytic leukemia (Pml) negatively regulates Akt in the nucleus. The tumor suppressor gene PTEN is commonly mutated or deleted in human cancers, leading to the phosphorylation and activation of the proto-oncogene protein kinase AKT (PKB). Phosphorylated AKT inactivates several transcription factors in the nucleus, but little is known about its regulation in this compartment. In Nature, Pandolfi and colleagues now show that the tumor suppressor promyelocytic leukemia (Pml) keeps nuclear Akt in check.
The authors found that the life expectancy of heterozygous double-knockout Pten+/- Pml+/- mice was markedly reduced compared to Pten+/- Pml+/+ mice; this is due to accelerated formation and progression of tumors in the colon and prostate. Interestingly, loss of Pml in these tissues increased the levels of nuclear phosphorylated Akt in Pten+/- mice. To determine whether Pml plays a role in Akt signaling, Pandolfi and colleagues assessed the status of Akt in Pml-/- mouse embryonic fibroblasts (MEFs). Serum stimulation of Pml-null cells enhanced the nuclear accumulation of phosphorylated Akt compared to wild type MEFs. This effect was rescued by PML expression, indicating that Pml may regulate Akt activation and localization. In agreement with these findings, the transcription factor FOXO3a, which is normally inactivated by Akt and exported from the nucleus, was predominantly found in the cytoplasm of Pml-/- cells after serum stimulation. Furthermore, the transcription of FOXO3a targets, such as the proapoptotic factor Bim and the DNA repair protein Gadd45, was decreased in the absence of Pml. So, how does Pml regulate Akt activity? Treatment of Pml+/+ MEFs with okadaic acid, which inhibits the only known Akt-Thr 308 phosphatase PP2a, increases the levels of phosphorylated Akt to those found in Pml-/- cells, suggesting that Pml inactivates Akt through PP2a. Indeed, both A and C subunits of PP2a co-precipitate with Pml; moreover, PP2a, Pml and Akt were found to co-localize in nuclear bodies of wild type MEFs but not in Pml-/- nuclei. In summary, this paper suggests that Pml inactivates nuclear Akt by increasing the interaction between phosphorylated Akt and PP2a in this cellular compartment, thereby preventing Akt-driven tumorigenesis. The results indicate that this function of Pml is especially important after Pten loss, and that tissues like prostate and colon are particularly sensitive to the levels of active Akt. Whether Pml is also involved in the recruitment of phosphorylated Akt to the nucleus remains to be investigated. Monica Hoyos-Flight
References | |
| ||||||||
| |||||||||||
 | |||||||||||
| |||||||||||
| |||||||||||
| |||||||||||
HOME | SIGNALING UPDATE | MOLECULE PAGES | DATA CENTER | ABOUT US | |||||||||||
| |||||||||||
