Background. The bcl‐2 protein has been shown to suppress apoptosis, and overexpression of the bcl‐2 protein has been reported in several malignant tumors. Skin is one of the largest organs in the body, and the most common human malignancies arise from keratinocytes in the epidermis. In this paper, the authors analyzed immunohistochemically the expression of the bcl‐2 protein in several keratinocytic (KC) tumors and inflammatory skin disorders to investigate the role of bcl‐2 in the development of benign and malignant skin tumors. Methods. Seventy‐two frozen tissues from patients with inflammatory KC proliferation (chronic dermatitis [CD] and psoriasis vulgaris [PV]), seborrheic keratosis (SK), carcinoma in situ of KC tumors (actinic keratosis [AK] and Bowen's disease [BD]), basal cell carcinoma (BCC), and squamous cell carcinoma (SCC), 2 SCC cell lines, and 20 normal skin were immunostained with an anti‐bcl‐2 monoclonal antibody. Results. Tissue with normal KC, CD, PV, and SK scarcely expressed the bcl‐2 protein. Seventy‐three percent of tissue with BD, 25% with AK, 67% with BCC, and 100% with SCC showed obvious bcl‐2 protein expression. bcl‐2 expression of BCC, BD, and SCC was restricted to the involved lesions, and surrounding normal tissue with KCs were bcl‐2 negative. Interestingly, tissue with atrophic AK expressed no bcl‐2 protein (none of five cases), whereas tissue with hypertrophic AK reacted weakly with the anti‐bcl‐2 antibody (two of three cases). Conclusions. bcl‐2 protein expression in patients with KC may be related to tumorigenic proliferation possibly due to enhanced cell survival, but not when inflammatory proliferation of keratinocytes is present.

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The N-terminal (1-83) fragment of the major constituent of plasma high-density lipoprotein, apolipoprotein A-I (apoA-I), strongly tends to form amyloid fibrils, leading to systemic amyloidosis. Here, using a series of deletion variants, we examined the roles of two major amyloidogenic segments (residues 14-22 and 50-58) in the aggregation and fibril formation of an amyloidogenic G26R variant of the apoA-I 1-83 fragment (apoA-I 1-83/G26R). Thioflavin T fluorescence assays and atomic force microscopy revealed that elimination of residues 14-22 completely inhibits fibril formation of apoA-I 1-83/G26R, whereas ⌬32-40 and ⌬50-58 variants formed fibrils with markedly reduced nucleation and fibril growth rates. CD measurements revealed structural transitions from random coil to ␤-sheet structures in all deletion variants except for the ⌬14-22 variant, indicating that residues 14-22 are critical for the ␤-transition and fibril formation. Thermodynamic analysis of the kinetics of fibril formation by apoA-I 1-83/G26R indicated that both nucleation and fibril growth are enthalpically unfavorable, whereas entropically, nucleation is favorable, but fibril growth is unfavorable. Interestingly, the nucleation of the ⌬50-58 variant was entropically unfavorable, indicating that residues 50-58 entropically promote the nucleation step in fibril formation of apoA-I 1-83/G26R. Moreover, a residue-level structural investigation of apoA-I 1-83/G26R fibrils with site-specific pyrene labeling indicated that the two amyloidogenic segments are in close proximity to form an amyloid core structure, whereas the N-and C-terminal tail regions are excluded from the amyloid core. These results provide critical insights into the aggregation mechanism and fibril structure of the amyloidogenic N-terminal fragment of apoA-I. Apolipoprotein (apoA-I) 3 is the major structural and functional constituent of plasma high-density lipoprotein (HDL) This work was partly supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant JP17H03979 (to H. S.). The authors declare that they have no conflicts of interest with the contents of this article. This article contains Figs. S1-S9.

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