Tethering by lamin A stabilizes and targets the ING1 tumour suppressor

Abstract

ING proteins interact with core histones through their plant homeodomains (PHDs) and with histone acetyltransferase (HAT) and histone deacetylase (HDAC) complexes to alter chromatin structure. Here we identify a lamin interaction domain (LID) found only in ING proteins, through which they bind to and colocalize with lamin A. Lamin knockout (LMNA(-/-)) cells show reduced levels of ING1 that mislocalize. Ectopic lamin A expression increases ING1 levels and re-targets it to the nucleus to act as an epigenetic regulator. ING1 lacking the LID does not interact with lamin A or affect apoptosis. In LMNA(-/-) cells, apoptosis is not affected by ING1. Mutation of lamin A results in several laminopathies, including Hutchinson-Gilford progeria syndrome (HGPS), a severe premature ageing disorder. HGPS cells have reduced ING1 levels that mislocalize. Expression of LID peptides to block lamin A-ING1 interaction induces phenotypes reminiscent of laminopathies including HGPS. These data show that targeting of ING1 to the nucleus by lamin A maintains ING1 levels and biological function. Known roles for ING proteins in regulating apoptosis and chromatin structure indicate that loss of lamin A-ING interaction may be an effector of lamin A loss, contributing to the HGPS phenotype.

TheCaenorhabditis elegans ing-3Gene Regulates Ionizing Radiation-Induced Germ-Cell Apoptosis in a p53-Associated Pathway

“…Similar localization of ING -3 and DAPI continued throughout the embryonic cell cycle, including during mitosis ( Figure 3B). This suggests that ING -3 is tightly bound to chromatin at all stages of the cell cycle and so differs from mammalian ING1, which is found throughout the cell during mitosis (Han et al 2008). ING -3 was also present in the gonad ( Figure 3C).…”

“…Comparison of the primary amino acid sequence of the ING3 proteins from different organisms showed that several regions appeared well conserved ( Figure 1A and supplemental Figure 1), including the PHD domain, the leucine zipper-like domain (LZL), the nuclear localization sequence (NLS, although it is in different locations in human and worm proteins), and the lamin interacting domain (LID, Soliman and Riabowol 2007;Han et al 2008).…”

Adenovirus-mediated expression of p33ING1b induces apoptosis and inhibits proliferation in gastric adenocarcinoma cells in vitro

“…ING1b also harbors three other domains: a proliferating cell nuclear antigen (PCNA) interacting protein motif (PIP) domain which binds PCNA following UV irradiation and is involved in apoptosis and cell cycle arrest, a lamin interaction domain (LID) which binds lamin A/HDAC complex to maintain its levels and biological function in the nucleus, and a partial bromodomain (PBD) which is commonly found in chromatin-associated protein [4]. Recently, it was found that serine 199 of p33…”

Role of ING Family Tumor Suppressors in Breast Cancer

“…All ING proteins contain nuclear conserved region (NCR) domain, which was identified by sequence analyses and is the second most highly conserved domain in the ING family proteins [15]. This N-terminal region of ING1 has been reported to interact directly with lamin A, suggesting that the association with nuclear lamina is a common feature of this family [27]. All ING proteins contain a nuclear localization signal (NLS) at the carboxy terminal, and some of ING proteins have multiple NLS.…”