Regulation of cell polarity determinants by the Retinoblastoma tumor suppressor protein.

Sandhya Payankaulam,Helen Mcneill,R William Henry,Kelvin Yeung,David N Arnosti

doi:10.1038/srep22879

Abstract

In addition to their canonical roles in the cell cycle, RB family proteins regulate numerous developmental pathways, although the mechanisms remain obscure. We found that Drosophila Rbf1 associates with genes encoding components of the highly conserved apical–basal and planar cell polarity pathways, suggesting a possible regulatory role. Here, we show that depletion of Rbf1 in Drosophila tissues is indeed associated with polarity defects in the wing and eye. Key polarity genes aPKC, par6, vang, pk, and fmi are upregulated, and an aPKC mutation suppresses the Rbf1-induced phenotypes. RB control of cell polarity may be an evolutionarily conserved function, with important implications in cancer metastasis.

Highlights

The Retinoblastoma tumor suppressor protein (RB) is a conserved central regulator of eukaryotic cell cycle, a function that has been extensively documented[1]
To understand the biological relevance of Rbf[1] interaction with cell polarity gene promoters, we tested whether depletion of Rbf[1] phenocopies polarity defects, such as those observed in fz, vang, and other core polarity mutants[18]
In ommatidia with the full complement of photoreceptor cells, a specific polarity phenotype was apparent, whereby the eight cells were canonically disposed, but their rotation and chirality was random, similar to the phenotype of planar cell polarity (PCP) mutants[20]. These rotation defects may reflect Rbf[1] regulation of core polarity genes, and/or regulation of another Rbf[1] target gene canoe, which is physically bound by Rbf1. canoe is an effector of the EGFR pathway, important for regulating ommatidial rotation in the eye[21,22]

Summary

Introduction

The Retinoblastoma tumor suppressor protein (RB) is a conserved central regulator of eukaryotic cell cycle, a function that has been extensively documented[1] (and references therein). In genome-wide studies, we found that Rbf[1] occupies a number of promoters for key genes linked to conserved cellular signaling pathways, including the insulin, Hippo, Jak /Stat and polarity pathways, in addition to canonical cell cycle genes[8]. Rbf[1] and the Hippo tumor suppressor pathway are functionally linked during photoreceptor differentiation. Molecular studies have linked RB to the insulin and mTOR signaling pathways[12,13] These studies suggest that RB plays a pivotal and evolutionarily conserved role in regulation of core signaling genes with pleiotropic roles in cell growth. We report evidence for direct functional links between Rbf[1] and conserved polarity genes, providing a novel molecular connection between regulation of cell cycle and cell polarity

Methods

Results

Conclusion