AIM1 , a novel non-lens member of the βγ-crystallin superfamily, is associated with the control of tumorigenicity in human malignant melanoma

Abstract

AIM1 is a novel gene whose expression is associated with the experimental reversal of tumorigenicity of human malignant melanoma. The predicted protein product of the major 4.1-kb transcript shows striking similarity to the ␤␥-crystallin superfamily. All known members of this superfamily contain two or four characteristic motifs arranged as one or two symmetrical domains. AIM1, in contrast, contains 12 ␤␥ motifs, suggesting a 6-domain structure resembling a trimer of ␤-or ␥-crystallin subunits. The structure of the AIM1 gene shows remarkable similarity to ␤-crystallin genes, with homologous introns delineating equivalent protein structural units. AIM1 is the first mammalian member of the ␤␥ superfamily with a primarily non-lens role. Other parts of the predicted AIM1 protein sequence have weak similarity with filament or actin-binding proteins. AIM1 is a good candidate for the putative suppressor of malignant melanoma on chromosome 6, possibly exerting its effects through interactions with the cytoskeleton. AIM1 (absent in melanoma) is a novel gene whose expression is altered in association with tumor suppression in a model of human melanoma (1). The AIM1 gene is localized to 6q21, within the putative chromosome 6 tumor suppressor region for human melanoma (2). Characterization of the AIM1 gene and its major transcripts reveals, unexpectedly, that AIM1 belongs to the ␤␥-crystallin (␤␥) superfamily.The optical properties of the eye lens largely depend on abundant soluble structural proteins, the crystallins (3-5). Although some crystallins are enzymes, the result of relatively recent gene recruitment events in distinct evolutionary lineages, other crystallins, related to stress-inducible proteins, have more ancient origins and are represented ubiquitously in all vertebrates (6, 7). This ubiquitous class includes the ␤-and ␥-crystallins, which are closely related in sequence and in gene and protein structure (8).Three non-lens members of the ␤␥ superfamily have been identified through a conserved sequence signature: Protein S of Myxococcus xanthus, a sporulating bacterium (9, 10); spherulin 3a of the slime mold Physarum polycephalum (11,12); and an epidermis differentiation-specific protein (EDSP or ep37) of the amphibian Cynops pyrrhogaster (13-15).The structure of Protein S has been confirmed by NMR analysis (16). The structure of a yeast killer toxin (WmKT) has also revealed unexpected similarity to the folding pattern of the ␤␥ superfamily (17). Although an ancestral relationship has been discussed, WmKT may represent an interesting example of evolutionary convergence.Except for spherulin 3a, and possibly WmKT, with two motifs, all other identified members of the ␤␥ superfamily have a 4-fold repeat of the characteristic ␤␥ motif. In contrast, AIM1 contains 12 ␤␥ motifs. Furthermore, the exon͞intron structure of the AIM1 gene shows remarkable similarity with ␤-crystallin genes, with each motif coded by a separate exon.Protein S, a calcium-binding protein of the bacterial spore coat, and spherulin 3a, a ...

Prognostic significance of allelic losses in primary melanoma

“…Although germline p16 INK4 (and p19 ARF ) mutations are present in some families with hereditary melanoma, p16 INK4 mutations are uncommon in sporadic melanoma, and while this gene may be inactivated via another mechanism (such as methylation or homozygous deletion) there is still some debate as to whether this is the sole target of 9p loss or whether there are additional relevant tumour suppressor genes on 9p (Fountain et al, 1992;Holland et al, 1994;Hussussian et al, 1994;Kamb et al, 1994;Ohta et al, 1994;Gruis et al, 1995a,b;Merlo et al, 1995;Puig et al, 1995;Quelle et al, 1995;Flores et al, 1996;Healy et al, 1996b;Kim et al, 1997;Wiest et al, 1997). Candidate tumour suppressor genes on 6q and 10q include AIM1 and PTEN/MMAC1 respectively, however, whether these genes are inactivated during primary cutaneous melanoma development and progression is unclear at present (Ray et al, 1997;Li et al, 1997;Steck et al, 1997).…”

Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies

“…Three other genes at this locus, C6orf203, PREP and AIM1, were marginally downregulated (between 2 and 1.5 fold), but only AIM1 has been implicated in tumor suppression in melanoma. 40 We, therefore, focused our attention on ATG5, PRDM1 and AIM1.…”

Calcium-binding Crystallins from Yersinia pestis

“…Some members of this superfamily are Protein S (2), Spherulin 3a (3,4), Streptomyces killer toxin-like protein (SKLP) (5), cargo proteins from Tetrahymena thermophila (6), AIM1 (absent in melanoma) (7), epidermis differentiation-specific proteins (8,9), yeast killer toxin WmKT (10), and Streptomyces metalloproteinase inhibitor (SMPI) (11). These members show structural similarity despite relatively low sequence identity, which reflects the functional diversity found among these proteins.…”