Abstract
The INhibitor of Growth 1 (ING1) is stoichiometric member of histone deacetylase (HDAC) complexes and functions as an epigenetic regulator and a type II tumor suppressor. It impacts cell growth, aging, apoptosis, and DNA repair, by affecting chromatin conformation and gene expression. Down regulation and mislocalization of ING1 have been reported in diverse tumor types and Ser/Thr phosphorylation has been implicated in both of these processes. Here we demonstrate that both in vitro and in vivo, the tyrosine kinase Src is able to physically associate with, and phosphorylate ING1, which results in a nuclear to cytoplasmic relocalization of ING1 in cells and a decrease of ING1 stability. Functionally, Src antagonizes the ability of ING1 to induce apoptosis, most likely through relocalization of ING1 and down regulation of ING1 levels. These effects were due to both kinase-dependent and kinase-independent properties of Src, and were most apparent at elevated levels of Src expression. These findings suggest that Src may play a major role in regulating ING1 levels during tumorigenesis in those cancers in which high levels of Src expression or activity are present. These data represent the first report of tyrosine kinase-mediated regulation of ING1 levels and suggest that kinase activation can impact chromatin structure through the ING1 epigenetic regulator.
Highlights
The INhibitor of Growth (ING) family of proteins are classified as type II tumor suppressors, and act as stoichiometric members of histone acetlytransferase (HAT) and histone deacetylase (HDAC) complexes [1]
Src Physically Interacts with INhibitor of Growth 1 (ING1) To ask if ING1 might serve as a substrate for Src, we performed immunoprecipitation-western assays to determine whether or not Src could physically interact with ING1
When ING1 was co-expressed with either WT, activated (Y530F) or kinasedead (K295M) versions of Src, the levels of ING1 associated with Src were reduced dramatically
Summary
The INhibitor of Growth (ING) family of proteins are classified as type II tumor suppressors, and act as stoichiometric members of histone acetlytransferase (HAT) and histone deacetylase (HDAC) complexes [1]. The first ING gene identified, human ING1, was discovered by PCR-mediated subtractive hybridization between normal mammary epithelial cells and breast cancer cells followed by a functional screen for tumorigenesis [4,5]. Different isoforms of ING1 are involved in various chromatin modification complexes, and each has unique functions. Inactivating one variant of ING1 in mice gave different outcomes than inactivating the whole gene [8,9], and in vitro ING1b expression induces apoptosis [10] while ING1a induces senescence [11]. The ING proteins have been found to function in many biological processes and affect growth regulation, apoptosis, aging, and DNA repair, largely through their ability to regulate histone acetylation, thereby affecting gene expression [6,7,12,13]
Sign-in/Register to view highlights & summary 
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