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1.  Structural and biochemical changes underlying a keratoderma-like phenotype in mice lacking suprabasal AP1 transcription factor function 
Cell Death & Disease  2015;6(2):e1647-.
Epidermal keratinocyte differentiation on the body surface is a carefully choreographed process that leads to assembly of a barrier that is essential for life. Perturbation of keratinocyte differentiation leads to disease. Activator protein 1 (AP1) transcription factors are key controllers of this process. We have shown that inhibiting AP1 transcription factor activity in the suprabasal murine epidermis, by expression of dominant-negative c-jun (TAM67), produces a phenotype type that resembles human keratoderma. However, little is understood regarding the structural and molecular changes that drive this phenotype. In the present study we show that TAM67-positive epidermis displays altered cornified envelope, filaggrin-type keratohyalin granule, keratin filament, desmosome formation and lamellar body secretion leading to reduced barrier integrity. To understand the molecular changes underlying this process, we performed proteomic and RNA array analysis. Proteomic study of the corneocyte cross-linked proteome reveals a reduction in incorporation of cutaneous keratins, filaggrin, filaggrin2, late cornified envelope precursor proteins, hair keratins and hair keratin-associated proteins. This is coupled with increased incorporation of desmosome linker, small proline-rich, S100, transglutaminase and inflammation-associated proteins. Incorporation of most cutaneous keratins (Krt1, Krt5 and Krt10) is reduced, but incorporation of hyperproliferation-associated epidermal keratins (Krt6a, Krt6b and Krt16) is increased. RNA array analysis reveals reduced expression of mRNA encoding differentiation-associated cutaneous keratins, hair keratins and associated proteins, late cornified envelope precursors and filaggrin-related proteins; and increased expression of mRNA encoding small proline-rich proteins, protease inhibitors (serpins), S100 proteins, defensins and hyperproliferation-associated keratins. These findings suggest that AP1 factor inactivation in the suprabasal epidermal layers reduces expression of AP1 factor-responsive genes expressed in late differentiation and is associated with a compensatory increase in expression of early differentiation genes.
PMCID: PMC4669787  PMID: 25695600
3.  Involvement of RARRES3 in the regulation of Wnt proteins acylation and signaling activities in human breast cancer cells 
Cell Death and Differentiation  2014;22(5):801-814.
The Wnt/β-catenin signaling pathway has emerged as a key regulator of complex biological processes, such as embryonic development, cell proliferation, cell fate decision and tumorigenesis. Recent studies have shown that the deregulation of Wnt/β-catenin signaling is frequently observed and leads to abnormal cell growth in human breast cancer cells. In this study, we identified a novel regulatory mechanism of Wnt/β-catenin signaling through RARRES3 that targets and modulates the acylation status of Wnt proteins and co-receptor low-density lipoprotein receptor-related protein 6, resulting in the suppression of epithelial–mesenchymal transition and cancer stem cell properties. Mutation of the conserved active site residues of RARRES3 indicates that RARRES3 serves as an acyl protein thioesterase that tethers its target proteins and modulates their acylation status. Furthermore, the functions of p53 in cell proliferation and Wnt/β-catenin signaling are significantly associated with the induction of RARRES3. Thus our findings provide a new insight into the molecular link between p53, protein acylation and Wnt/β-catenin signaling whereby RARRES3 plays a pivotal role in modulating the acylation status of signaling proteins.
PMCID: PMC4392077  PMID: 25361079
4.  Molecular biology of keratinocyte differentiation. 
Epidermal keratinocytes (skin cells) are highly specialized epithelial cells designed to perform a very specific function, separation of the organism from its environment. To accomplish this the cells synthesize precursors and assemble them into two distinct structures, the cornified envelope and keratin intermediate filaments. The intermediate filaments are assembled from keratin monomers and the cornified envelope is assembled from a protein called involucrin and several other proteins. Expression of involucrin and the keratins genes are regulated as a function of the stage of keratinocyte differentiation and by various external agents such as calcium and vitamin A. To study the function of these structures and the regulation of precursor production we have cloned cDNA and genomic clones encoding involucrin and four of the keratin polypeptides. Retinoids profoundly alter the differentiation pattern of human epidermal keratinocytes, but the underlying biochemical basis of this change is not known. In this report we describe retinoid-promoted changes in keratin gene expression that may, in part, be responsible for the alteration in cellular phenotype in the presence of the vitamin. We also describe the novel structure of the human 40 kD keratin, a member of the keratin family that is retinoid responsive and is likely to be important during epidermal development. Finally, we describe the structure of the envelope precursor protein, involucrin, as determined from its DNA sequence and speculate on its role in cornified envelope formation.
PMCID: PMC1567608  PMID: 2466639

Results 1-4 (4)