Rice, Robert - Research

The first direction of our work is to understand the molecular basis of keratinocyte differentiation, including the regulation of specific markers and the coordination of marker expression. To this end, we have investigated the transcriptional regulation of two markers, involucrin and keratinocyte transglutaminase (1,2). The latter, a membrane bound enzyme (3), stabilizes the cross-linked envelope of mature epidermal cells by cross-linking a variety of proteins including involucrin, a major substrate in cultured keratinocytes (4,5). Lack of functional transglutaminase results in a debilitating skin disease, lamellar ichthyosis, in which the lack of isopeptide cross-linking is evident in mature cells of epidermis and appendages (6). The molecular bases of such afflictions may be clarified by characterization of transglutaminase-cross-linked structures in mature keratinocytes (7). The second direction of our work involves studying mechanisms by which toxic agents perturb keratinocyte function. Carcinogens and tumor promoters such as arsenic and dioxin (TCDD) have remarkable effects on epidermal differentiation (8-11) as do physiological conditions such as oxygen tension (12). Elucidating the mechanisms by which these agents act is important for assessing the risk of exposure to such toxins in our environment, and will also help understand keratinocyte programming. Most of the work in the lab employs human keratinocytes derived from normal epidermis or squamous cell carcinomas, which in some cases show striking differences in properties such as transcription factor localization (13). In addition, spontaneously immortalized keratinocytes have proven useful for studying the consequences of elevation of endogenous telomerase activity (14). Epithelial cells from a variety of rat tissues, exhibiting a keratinocyte phenotype in culture (15,16), permit studies of species differences in biotransformation and toxic response (17,18). Proteomic analysis of epidermis and appendages is under study to understand keratinocyte maturation and as a potential diagnostic aid (19,20).

1.  Phillips MA, Jessen BA, Lu Y, Qin Q, Stevens ME, Rice RH (2004) A distal region of the human TGM1 promoter is required for expression in transgenic mice and cultured keratinocytes. BioMed Central Dermatology 4(1):2

2.  Phillips MA, Qin Q, Rice RH (2000) Identification of an involucrin promoter transcriptional response element with activity restricted to keratinocytes. Biochem J 348:45-53

3.  Phillips MA, Qin Q, Mehrpouyan M, Rice RH (1993) Keratinocyte transglutaminase membrane anchorage: Analysis of site-directed mutants. Biochemistry 32:11057-11063

4.  Rice RH, Green H (1979) Presence in human epidermal cells of a soluble protein precursor of the cross-linked envelope: Activation of the cross-linking process by calcium ions. Cell 18:681-694

5.  Thacher SM, Rice RH (1985) Keratinocyte-specific transglutaminase of cultured human epidermal cells: Relation to cross-linked envelope formation and terminal differentiation. Cell 40:685-695

6.  Rice RH, Crumrine D, Uchida Y, Gruber R, Elias PM (2005) Structural changes in epidermal scale and appendages as indicators of defective TGM1 activity. Arch Dermatol Res 297:127-133

7.  Lee YJ, Rice RH, Lee YM (2006) Proteome analysis of human hair shaft: From protein identification to posttranslational modification. Molec Cell Proteomics 5:789-800

8.  Patterson TJ, Rice RH (2007) Arsenite and insulin exhibit opposing effects on epidermal growth factor receptor and keratinocyte proliferative potential. Toxicol Appl Pharmacol 221:119-128

9.  Reznikova TV, Phillips MA, Patterson TJ, Rice RH (2010) Opposing actions of insulin and arsenite converge on PKCδ to alter keratinocyte proliferative potential and differentiation. Molec Carcinogenesis 49:398-409

10.  Hu Q, Rice RH, Qin Q, Phinney BS, Eigenheer RA, Bao W, Zhao B (2013) Proteomic analysis of human keratinocyte response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. J Proteome Res 12:5340-5347

11.  Phillips MA, Qin Q, Hu Q, Zhao B, Rice RH (2013) Arsenite suppression of BMP signaling in human keratinocytes. Toxicol Appl Pharmacol 269:290-296

12.  Ngo MA, Sinitsyna NN, Qin Q, Rice RH (2007) Oxygen-dependent differentiation of human keratinocytes. J Invest Dermatol 127:354-361

13.  Mazina OM, Phillips MA, Williams T, Vines CA, Cherr GN, Rice RH (2001) Redistribution of transcription factor AP-2α in differentiating cultured human epidermal cells. J Invest Dermatol 117:864-870

14.  Rea MA, Zhou L, Qin Q, Barrandon Y, Easley K, Gungner S, Phillips MA, Holland WS, Gumerlock PH, Rocke DM, Rice RH (2006) Spontaneous immortalization of human epidermal cells with naturally elevated telomerase. J Invest Dermatol 126:2507-2515

15.  Phillips MA, Rice RH (1983) Convergent differentiation in cultured rat cells from nonkeratinized epithelia: Keratinocyte character and intrinsic differences. J Cell Biol 97:686-691

16.  Parenteau NL, Pilato A, Rice RH (1986) Induction of keratinocyte type I transglutaminase in epithelial cells of the rat. Differentiation 33:130-141

17.  Chun HS, Kuzmicky PA, Kado NY, Rice RH (2000) Toxicity of Trp-P-2 to cultured human and rat keratinocytes. Chem-Biol Interact 127:237-253

18.  Monk, SA, Denison MS, Rice RH (2003) Reversible stepwise negative regulation of CYP1A1 in cultured rat epidermal cells. Arch Biochem Biophys 419:158-169

19.  Rice RH, Bradshaw KM, Durbin-Johnson BP, Rocke DM, Eigenheer RA, Phinney BS, Sundberg JP (2012) Differentiating inbred mouse strains from each other and those with single gene mutations using hair proteomics. PLoS One 7(12):e51956

20.  Rice RH, Bradshaw KM, Durbin-Johnson BP, Rocke DM, Eigenheer RA, Phinney BS, Schmuth M, Gruber R (2013) Distinguishing ichthyoses by protein profiling. PLoS ONE 8(10):e75355