Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage

Carrera, Samantha; Cuadrado-Castano, Sara; Samuel, Jesvin; Jones, George D.D.; Villar, Enrique; Lee, S W; Macip, Salvador

doi:10.1038/cdd.2013.14

Cited by 34 publications

(35 citation statements)

References 44 publications

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“…We considered potential mechanisms for the decrease in STRA6 expression. STRA6 has been shown to be induced by retinoic acid (10-12), Wnt-1 (12), and p53 (60). However, these mechanisms do not appear to explain the marked decrease in STRA6 in adipose tissue of high-fat-diet-fed mice or ob/ob mice since retinoic acid levels and retinoic acid receptor signaling are not reduced in adipose tissue in these models (61; data not shown).…”

Section: Discussionmentioning

confidence: 81%

Downregulation of STRA6 in Adipocytes and Adipose Stromovascular Fraction in Obesity and Effects of Adipocyte-Specific STRA6 Knockdown In Vivo

Zemany

Kraus

Norseen

et al. 2014

Molecular and Cellular Biology

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bTo investigate the mechanisms by which elevated retinol-binding protein 4 (RBP4) causes insulin resistance, we studied the role of the high-affinity receptor for RBP4, STRA6 (stimulated by retinoic acid), in insulin resistance and obesity. In high-fat-diet-fed and ob/ob mice, STRA6 expression was decreased 70 to 95% in perigonadal adipocytes and both perigonadal and subcutaneous adipose stromovascular cells. To determine whether downregulation of STRA6 in adipocytes contributes to insulin resistance, we generated adipose-Stra6 ؊/؊ mice. Adipose-Stra6 ؊/؊ mice fed chow had decreased body weight, fat mass, leptin levels, insulin levels, and adipocyte number and increased expression of brown fat-selective markers in white adipose tissue. When fed a highfat diet, these mice had a mild improvement in insulin sensitivity at an age when adiposity was unchanged. STRA6 has been implicated in retinol uptake, but retinol uptake and the expression of retinoid homeostatic genes (encoding retinoic acid receptor ␤ [RAR␤], CYP26A1, and lecithin retinol acyltransferase) were not altered in adipocytes from adipose-Stra6 ؊/؊ mice, indicating that retinoid homeostasis was maintained with STRA6 knockdown. Thus, STRA6 reduction in adipocytes in adipose-Stra6 ؊/؊ mice fed chow resulted in leanness, which may contribute to their increased insulin sensitivity. However, in wild-type mice with high-fat-diet-induced obesity and in ob/ob mice, the marked downregulation of STRA6 in adipocytes and adipose stromovascular cells does not compensate for obesity-associated insulin resistance.T hree hundred fifty million people worldwide have diabetes (1), and the impact will be staggering if we do not develop more effective methods for early detection and treatment. Serum retinol-binding protein 4 (RBP4) is elevated in humans and rodents with insulin resistance and type 2 diabetes (2-4), and data suggest that it may play a causative role (4, 5). Injection of purified RBP4 or overexpression of RBP4 in mice causes insulin resistance (4). Furthermore, a gain-of-function polymorphism in the RBP4 promoter is associated with an 80% increased risk of developing diabetes in humans (5). In addition, epidemiologic studies in several ethnic backgrounds indicate that elevated RBP4 is an early marker of prediabetes (6) and metabolic syndrome (7,8) and is associated with a 3.6-fold increased risk of myocardial infarction (9).The mechanisms by which RBP4 causes insulin resistance and whether the actions of RBP4 depend on a receptor are questions of high interest in the field. STRA6 is a high-affinity cell surface receptor for RBP4 that mediates vitamin A uptake (10). STRA6 is highly expressed in blood-organ barriers and in the brain, eye, kidney, testis, and female reproductive tract, and it is absent from the liver (11). STRA6 is upregulated in some tumors, and its expression can be induced by retinoids and increased Wnt-1 expression in mammary epithelial cells (12). RBP4 mediates insulin resistance through STRA6-independent (13, 14) and STRA6-dependent pathwa...

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Section: Discussionmentioning

confidence: 81%

Downregulation of STRA6 in Adipocytes and Adipose Stromovascular Fraction in Obesity and Effects of Adipocyte-Specific STRA6 Knockdown In Vivo

Zemany

Kraus

Norseen

et al. 2014

Molecular and Cellular Biology

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“…A total of 40,000 cells were processed as described (35). Briefly, 170 mL of 0.6% low melting point agarose was added to the cell pellet.…”

Section: Comet Assaymentioning

confidence: 99%

BTK Modulates p53 Activity to Enhance Apoptotic and Senescent Responses

et al. 2016

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Abstractp53 is a tumor suppressor that prevents the emergence of transformed cells by inducing apoptosis or senescence, among other responses. Its functions are regulated tightly by posttranslational modifications. Here we show that Bruton's tyrosine kinase (BTK) is a novel modulator of p53. We found that BTK is induced in response to DNA damage and p53 activation. BTK induction leads to p53 phosphorylation, which constitutes a positive feedback loop that increases p53 protein levels and enhances the transactivation of its target genes in response to stress. Inhibiting BTK reduced both p53-dependent senescence and apoptosis. Further, BTK expression also upregulated DNA damage signals and apoptosis. We conclude that despite being involved in oncogenic signals in blood malignancies, BTK has antineoplastic properties in other contexts, such as the enhancement of p53's tumor suppressor responses. Along with evidence that BTK expression correlates with good prognosis in some epithelial tumors, our findings may encourage a reevaluation of the clinical uses of BTK inhibitors in cancer therapy.

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“…Analysis of oxidatively damaged purine DNA base lesion levels was done using the enzyme-modified comet assay protocol, as described previously (31). After lysis, slides were washed once with distilled water and immersed in three changes of enzyme digestion buffer [40 mmol/L HEPES, 0.1 mol/L KCl, 0.5 mmol/L EDTA, and 0.2 mg/mL BSA (pH 8.0)], for 5 minutes each time at room temperature.…”

Section: Measurement Of Oxidative Damage To Dnamentioning

confidence: 99%

Posttranscriptional Upregulation of p53 by Reactive Oxygen Species in Chronic Lymphocytic Leukemia

et al. 2016

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Chronic lymphocytic leukemia (CLL) cells multiply and become more resistant to immunochemotherapy in "proliferation centers" within tissues, whereas apoptosis occurs in the periphery. Various models recapitulate these microenvironments in vitro, such as stimulation with CD154 and IL4. Using this system, we observed a 30-to 40-fold induction of wild-type p53 protein in 50 distinct human CLL specimens tested, without the induction of either cell-cycle arrest or apoptosis. In contrast, the mRNA levels for p53 did not increase, indicating that its elevation occurred posttranscriptionally. Mechanistic investigations revealed that under the conditions studied, p53 was phosphorylated on residues associated with p53 activation and increased half-life. However, p53 protein induced in this manner could transcriptionally activate only a subset of target genes. The addition of a DNAdamaging agent further upregulated p53 protein levels, which led to apoptosis. p53 induction relied on the increase in intracellular reactive oxygen species observed after CD154 and IL4 stimulation. We propose that chronic oxidative stress is a characteristic of the microenvironment in B-cell "proliferation centers" in CLL that are capable of elevating the basal expression of p53, but to levels below the threshold needed to induce arrest or apoptosis. Our findings suggest that reactivation of the full transcriptional activities of p53 in proliferating CLL cells may offer a possible therapeutic strategy.

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Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage

Cited by 34 publications

References 44 publications

Downregulation of STRA6 in Adipocytes and Adipose Stromovascular Fraction in Obesity and Effects of Adipocyte-Specific STRA6 Knockdown In Vivo

Downregulation of STRA6 in Adipocytes and Adipose Stromovascular Fraction in Obesity and Effects of Adipocyte-Specific STRA6 Knockdown In Vivo

BTK Modulates p53 Activity to Enhance Apoptotic and Senescent Responses

Posttranscriptional Upregulation of p53 by Reactive Oxygen Species in Chronic Lymphocytic Leukemia

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