Phylogenetic Analysis of the ING Family of PHD Finger Proteins

Abstract

Since the discovery of ING1 class II tumor suppressors in 1996, five different ING genes (ING1 to ING5) encoding proteins with highly conserved plant homeodomain (PHD) motifs and several splicing isoforms of the ING1 and ING2 gene have been identified. The ING family functions in DNA repair and apoptosis in response to UV damage through binding to proliferating cell nuclear antigen (PCNA); chromatin remodeling and regulation of gene expression through regulating and/or targeting histone acetyltransferase/deacetylase (HAT/HDAC) activities; binding targets of rare phosphatidylinositol phosphates (PtdInsPs) that function in DNA damage-initiated stress signaling; and regulating brain tumor angiogenesis through transcriptional repression of NF-KB-responsive genes. To elucidate the evolutionary history of ING proteins and summarize what is known about regions highly conserved in the ING family members, we have examined the sequences and phylogenetic relationships of ING proteins across taxonomically diverse organisms. We have identified novel ING family members in rats, frogs, fish, mosquitoes, fruit flies, worms, fungi, and plants. We have also clarified the naming and classification of ING proteins based on our phylogenetic analysis to allow better understanding of the ING protein family. Using sequence similarities, we have identified novel regions and motifs of unknown function that are conserved across family members. An evolutionary history for the ING family of PHD finger proteins is presented that indicates that five ING genes are present in vertebrates. Three of these may be paralogs of ING genes found in arthropods, whereas nematodes, fungi, and green plants contain ING genes that have general features of the vertebrate ING family.

Detection of novel mRNA splice variants of human ING4 tumor suppressor gene

“…Alternative splicing also has been described for ING genes. In particular human ING1 gene encodes four proteins, differing at the N-terminus and exerting distinct functions (He et al, 2005). In addition, multiple variants of ING1 and ING2 have been identified in Xenopus laevis .…”

“…The amino-acid sequence alignment of human ING proteins revealed few conserved regions: a Leucin Zipper-like (LZL) motif, probably involved in proteinprotein interaction, located at the N-terminus of all ING proteins but ING1; a bipartite nuclear localization signal (NLS), containing two clusters of basic amino acids; and a C-terminal plant homeo-domain (PHD), a Cys4-His-Cys3 zinc finger motif spanning 50-80 residues, found in many nuclear proteins such as transcription factors and proteins regulating chromatin structure (He et al, 2005;Russell et al, 2006). ING2 PHD domain interacts with phosphoinositides, thus regulating the capability of ING2 to activate p53 (Gozani et al, 2003).…”

“…The ING4 gene, located at chromosome 12p13.31, consists of eight exons and encodes a 29-kDa protein expressed in multiple human tissues (Garkavtsev et al, 2004;Gunduz et al, 2005;He et al, 2005). Allelic loss of ING4 locus has been reported in head and neck squamous cell carcinomas and in breast tumors (Kim et al, 2004;Gunduz et al, 2005).…”

Inhibitor of growth 4 (ING4) is up-regulated by a low K intake and suppresses renal outer medullary K channels (ROMK) by MAPK stimulation

“…ING4 is a member of the ING tumor-suppressor family proteins, which regulate cell cycle (16), transcription, DNA repair, oncogenesis, and apoptosis (8). Although homology among the five members (ING1-5) is low, all ING family proteins have a highly conserved plant homeodomain finger motif that has been demonstrated to modulate ubiquitination (17) and to associate with phosphatidylinositol phosphate (18).…”

“…They have been shown to regulate cell cycle, transcription and oncogenesis (8), and to promote UV-induced apoptosis of skin cells (9). ING4 also plays an important role in inhibiting tumor growth and angiogenesis in brain tumor cells (10).…”