PMC

Schematic view of ING factors as coregulators of AR in PC. Androgens (black circle) bind to AR that translocates into the nucleus. ING1 and ING2 proteins interact with AR and serve as AR corepressors leading to reduced AR target gene expression of positively regulated AR target genes. Furthermore, ING1 and ING2 mediate the transrepression of the AR silenced target gene, hTERT []. On the other hand, ING3 acts as AR-coactivator, as it recruits Tip60 to AR that becomes acetylated (Ac), leading to enhanced transactivation.

Domains of ING protein isoforms. ING proteins are well conserved throughout evolution. The plant homeodomain (PHD) allows these proteins to bind to the H3K4me3 histone mark and is present in all INGs. The lamin interacting domain (LID) is important so they can interact with lamin A and, at least for ING1, maintain nuclear morphology. Located within the nuclear localization sequence (NLS) that promotes translocation of the ING proteins to the nucleus by binding the karyopherin proteins are small, basic nucleolar targeting sequences (NTS). These direct ING1 to the nucleoli under conditions of stress, which promotes apoptosis. The NLS can also bind the p53 tumor suppressor. Proliferating cell nuclear antigen protein (PCNA) has been shown to bind specifically to ING1b via the PCNA-interacting protein (PIP) motif, and this interaction is also important for promoting apoptosis in response DNA-damage-induced stress. The polybasic region (PBR) is present only in ING1 and ING2. This motif can interact with both bioactive signaling phospholipids (PIs) and ubiquitin (Ub), the latter of which might serve to stabilize multi-monoubiquitination p53. The function of the partial bromodomain (PBD) has not been defined, but like the leucine zipper-like (LZL) region, may promote ING protein multimerization and/or interaction with other members of the HAT and HDAC complexes that ING proteins target to the H3K4Me3 histone mark.

Structure of ING proteins in Homo sapiens. Each ING protein with its name and encoding major variants is listed on the left. The characterized domain composition, approximate location, is shown on the right. All ING proteins contain three conserved regions, a PHD (plant homeodomain), NLS (nuclear localization signal), and NCR (novel conserved region) from C-terminal region to N-terminal region. An LZL (leucine zipper-like domain) is present in ING2-5. p33^ING1b also have a PIP (PCNA-Interacting Protein Motif) domain through which it binds to PCNA following UV irradiation, a PBD (partial bromodomain) which commonly found in chromatin-associated protein, and an LID (Lamin Interaction domain). p33^ING1b binds to lamin A/HDAC complexes via LID to maintain its levels and biological function in nucleus. Additionally, phosphorylation sites were found at serine 199 of p33^ING1b. 14-3-3 bind to phosphorylated serine 199 result in translocation of p33^ING1b from the nucleus to the cytoplasm.

A schematic diagram of the ING protein family members involved in chromatin remodeling. Chromatin compaction is modulated via posttranslational modifications including histone methylation (silent chromatin) as well as histone acetylation (active chromatin). By binding to the histone mark H3K4me3, ING1b recruits the HDAC mSin3A/HDAC1/2 complex or Gadd45a, for local histone deacetylation. ING2a, in complex with HDAC1/2, SAP30 and mSin3A can bind either H3K4me3 or H3K9me3. ING3 can acetylate the N-terminal tails of histones H4 and H2A. Moreover, ING4 and ING5 are in complex with MYST-HB01-JADE-hEAF6-HAT. ING5 is also a component of another HAT complex (MOZ/MORF-MYST-HAT) [, ]