Abstract

Strict regulation of proliferation is vital for development, whereas unregulated cell proliferation is a fundamental characteristic of cancer. The polarity protein atypical protein kinase C lambda/iota (aPKCλ) is associated with cell proliferation through unknown mechanisms. In endothelial cells, suppression of aPKCλ impairs proliferation despite hyperactivated mitogenic signaling. Here we show that aPKCλ phosphorylates the DNA binding domain of forkhead box O1 (FoxO1) transcription factor, a gatekeeper of endothelial growth. Although mitogenic signaling excludes FoxO1 from the nucleus, consequently increasing c-Myc abundance and proliferation, aPKCλ controls c-Myc expression via FoxO1/miR-34c signaling without affecting its localization. We find this pathway is strongly activated in the malignant vascular sarcoma, angiosarcoma, and aPKC inhibition reduces c-Myc expression and proliferation of angiosarcoma cells. Moreover, FoxO1 phosphorylation at Ser218 and aPKC expression correlates with poor patient prognosis. Our findings may provide a potential therapeutic strategy for treatment of malignant cancers, like angiosarcoma.

Highlights

  • Strict regulation of proliferation is vital for development, whereas unregulated cell proliferation is a fundamental characteristic of cancer

  • APKCλ is a negative regulator of vascular endothelial growth factors (VEGFs) signaling, loss of aPKCλ in endothelial cells (ECs) results in decreased proliferation[17]

  • To begin to understand this conundrum, we examined the expression of Forkhead box O1 (FoxO1) and c-Myc in the retinal vasculature at postnatal day 6 (P6) in control and EC specific inducible aPKCλ loss of function (PrkciiΔEC) mice (Fig. 1a, b)

Read more

Summary

Introduction

Strict regulation of proliferation is vital for development, whereas unregulated cell proliferation is a fundamental characteristic of cancer. Mitogenic signaling excludes FoxO1 from the nucleus, increasing cMyc abundance and proliferation, aPKCλ controls c-Myc expression via FoxO1/miR-34c signaling without affecting its localization. We find this pathway is strongly activated in the malignant vascular sarcoma, angiosarcoma, and aPKC inhibition reduces c-Myc expression and proliferation of angiosarcoma cells. Laboratory for Cell Polarity and Organogenesis, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany. Our study reveals that aPKC controls physiological and pathological vascular growth by regulating the transcriptional activity and abundance of key transcription factors FoxO1 and cMyc. we show that abnormal aPKC/FoxO1/c-Myc signaling contributes to excessive EC proliferation in angiosarcoma

Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call