Identification and characterization of the retinoic acid response elements in the human RIG1 gene promoter

Journal of Investigative Dermatology

Adhikary

Shaw

et al. 2014

TIG3 is a tumor suppressor protein that plays a key role in controlling cell proliferation. TIG3 is observed at reduced levels in epidermal squamous cell carcinoma, and restoration of expression in skin cancer cells reduces cell survival. TIG3 suppresses cell survival via mechanisms that involve localization at the plasma membrane and at the centrosome. TIG3 interacts at the plasma membrane to activate enzymes involved in keratinocyte terminal differentiation, and at the centrosome to inhibit daughter centrosome separation during mitosis leading to cessation of cell proliferation and induction of apoptosis. An important goal is identifying the motifs required for TIG3 localization at these intracellular sites as a method to understand the function of TIG3 at each location. TIG3 encodes an N-terminal hydrophilic region (amino acids 1–135) and a C-terminal membrane anchoring domain (amino acids 135–164). We show that the C-terminal hydrophobic domain targets intact TIG3 to the plasma membrane, but when isolated as an independent element localizes at the mitochondria. We further demonstrate that a segment of the N-terminal hydrophilic region targets the centrosome. These studies provide important insights regarding the mechanisms that guide subcellular localization of this keratinocyte survival regulator.

Section: Introductionmentioning

confidence: 99%

Pericentrosomal Localization of the TIG3 Tumor Suppressor Requires an N-Terminal Hydrophilic Region Motif

Journal of Investigative Dermatology

Adhikary

Shaw

et al. 2014

“…Also known as RIG1 and H-Rev107-2 (Huang et al, 2000;Jiang et al, 2005;Ou et al, 2008;Tsai et al, 2006;Tsai et al, 2007), TIG3 displays homology to the human, mouse and rat forms of Hrev107, and is a member of the H-rev family of class II tumor suppressors, and the NlpC and P60 superfamily (Deucher et al, 2000;DiSepio et al, 1998). These proteins include an N-terminal hydrophilic domain and a C-terminal membrane-anchoring domain (Deucher et al, 2000;DiSepio et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

TIG3 Interaction at the Centrosome Alters Microtubule Distribution and Centrosome Function

Journal of Cell Science

Jiang

Martin

et al. 2012

SummaryTIG3 is an important pro-differentiation regulator that is expressed in the suprabasal epidermis. We have shown that TIG3 activates selective keratinocyte differentiation-associated processes leading to cornified envelope formation. However, TIG3 also suppresses cell proliferation by an unknown mechanism. Our present studies suggest that cessation of growth is mediated through the impact of TIG3 on the centrosome and microtubules. The centrosome regulates microtubule function in interphase cells and microtubule spindle formation in mitotic cells. We show that TIG3 colocalizes with c-tubulin and pericentrin at the centrosome. Localization of TIG3 at the centrosome alters microtubule nucleation and reduces anterograde microtubule growth, increases acetylation and detyrosination of a-tubulin, increases insoluble tubulin and drives the formation of a peripheral microtubule ring adjacent to the plasma membrane. In addition, TIG3 suppresses centrosome separation, but not duplication, and reduces cell proliferation. We propose that TIG3 regulates the formation of the peripheral microtubule ring observed in keratinocytes of differentiated epidermis and also has a role in the cessation of proliferation in these cells.

“…TIG3, also known as retinoid induced gene 1 (RIG1) and retinoic acid receptor responder 3 (RARRES3), is a tumor suppressor protein composed of 164 amino acids (Ou et al , 2008; Jiang et al , 2005; Tsai et al , 2007; Huang et al , 2000). TIG3 was discovered as expressed in keratinocyte treated with the synthetic retinoid, tazarotene (DiSepio et al , 1998).…”

Section: Tazarotene Induced Genementioning

confidence: 99%

“…Based on this information, restoration of TIG3 expression in hyperproliferative diseases would be predicted to reduce cell proliferation and survival. Endogenous TIG3 levels can be increased by treating cells with tazarotene or other retinoids (Jiang et al , 2005; Huang et al , 2000; DiSepio et al , 1998; Higuchi et al , 2003). Retinoid-dependent increased TIG3 expression is also observed in retinoid-treated psoriatic lesions (Duvic et al , 2000; Duvic et al , 2003; Talpur et al , 2009).…”

Section: Tig3 In Hyperproliferative Diseasementioning

confidence: 99%

TIG3: An Important Regulator of Keratinocyte Proliferation and Survival

Journal of Investigative Dermatology

Eckert

2014

Tazarotene induced gene 3 (TIG3) is a tumor suppressor protein. In normal human epidermis, TIG3 is present in the differentiated, suprabasal layers and regulates terminal differentiation. TIG3 level is reduced in hyperproliferative diseases, including psoriasis and skin cancer, suggesting that loss of TIG3 is associated with enhanced cell proliferation. Moreover, transient expression of TIG3 leads to terminal differentiation in normal keratinocytes and apoptosis in skin cancer cells. In both cell types, TIG3 distributes to the cell membrane and to the centrosome. At the cell membrane, TIG3 interacts with and activates type I transglutaminase (TG1) to enhance keratinocyte terminal differentiation. TIG3 at the centrosome acts to inhibit centrosome separation during mitosis and to alter microtubule function. These findings argue that TIG3 is involved in control of keratinocyte differentiation and that loss of TIG3 in transformed cells contributes to the malignant phenotype.