Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Mechanisms Underlying the Regulation of HP1I? by the NGF-PKA Signaling Pathway. Sci Rep 2018 10 10;8(1):15077

Date

10/12/2018

Pubmed ID

30305677

Pubmed Central ID

PMC6180112

DOI

10.1038/s41598-018-33475-y

Scopus ID

2-s2.0-85054625299   2 Citations

Abstract

Heterochromatin protein 1 I? (HP1I?) is a well-known chromatin protein, which regulates gene silencing during the execution of processes associated with embryogenesis, organ maturation, and cell differentiation. We find that, in vivo, the levels of HP1I? are downregulated during nervous system development. Similar results are recapitulated in vitro during nerve growth factor (NGF)-induced neuronal cell differentiation in PC12 cells. Mechanistically, our experiments demonstrate that in differentiating PC12 cells, NGF treatment decreases the association of HP1I? to silent heterochromatin, leads to phosphorylation of this protein at S83 via protein kinase A (PKA), and ultimately results in its degradation. Genome-wide experiments, using gain-of-function (overexpression) and loss-of-function (RNAi) paradigms, demonstrate that changing the level of HP1I? impacts on PC12 differentiation, at least in part, through gene networks involved in this process. Hence, inactivation of HP1I? by different post-translational mechanisms, including reduced heterochromatin association, phosphorylation, and degradation, is necessary for neuronal cell differentiation to occur. Indeed, we show that theA increaseA of HP1I? levels has the reverse effect, namely antagonizing neuronal cell differentiation, supporting that this protein acts as a barrier for this process. Thus, these results describe the regulation and participation of HP1I? in a novel membrane-to-nucleus pathway, through NGF-PKA signaling, which is involved in NGF-induced neuronal cell differentiation.

Author List

Seo S, Mathison A, Grzenda A, Podratz J, Calvo E, Brimijoin S, Windebank A, Iovanna J, Lomberk G, Urrutia R

Authors

Gwen Lomberk PhD Professor in the Surgery department at Medical College of Wisconsin
Angela Mathison PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Aging
Amino Acid Sequence
Animals
Cell Differentiation
Chromosomal Proteins, Non-Histone
Cyclic AMP-Dependent Protein Kinases
Down-Regulation
Female
Gene Regulatory Networks
Genome
Humans
Male
Mice, Inbred C57BL
Nerve Growth Factor
Nervous System
Neurites
PC12 Cells
Phosphorylation
Phosphoserine
Rats
Serum
Signal Transduction