Clinical Utility of KAP-1 Expression in Thyroid Lesions

Martins, Mariana Bonjiorno; Marcello, Marjory Alana; Morari, Elaine Cristina; Cunha, Lucas Leite; Soares, Fernando Augusto; Vassallo, José; Ward, Laura Sterian

doi:10.1007/s12022-013-9245-z

Cited by 11 publications

(8 citation statements)

References 29 publications

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“…In addition, TRIM28 has been shown to suppress the activity of the oncogenic transcription factors HIF-1α and STAT3 [44,45], and to de-repress the transcription of major pro-apoptotic genes of the BCL-2 family including BAX, PUMA and NOXA [46]. Conversely, TRIM28 level has been linked to poor prognosis in gastric cancer and thyroid carcinoma [47][48][49] and TRIM28 has been reported to ubiquitinate and eliminate p53 and AMPK, two factors that participate in tumor suppression [27,28]. However, in the latter cases, the E3-ubiquitin ligase activity of TRIM28 requires the presence of MAGE cofactors [50], which is not the case for TRIM28-mediated ubiquitination of BCL2A1.…”

Section: Discussionmentioning

confidence: 99%

TRIM17 and TRIM28 antagonistically regulate the ubiquitination and anti-apoptotic activity of BCL2A1

et al. 2018

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BCL2A1 is an anti-apoptotic member of the BCL-2 family that contributes to chemoresistance in a subset of tumors. BCL2A1 has a short half-life due to its constitutive processing by the ubiquitin-proteasome system. This constitutes a major tumor-suppressor mechanism regulating BCL2A1 function. However, the enzymes involved in the regulation of BCL2A1 protein stability are currently unknown. Here, we provide the first insight into the regulation of BCL2A1 ubiquitination. We present evidence that TRIM28 is an E3 ubiquitin-ligase for BCL2A1. Indeed, endogenous TRIM28 and BCL2A1 bind to each other at the mitochondria and TRIM28 knock-down decreases BCL2A1 ubiquitination. We also show that TRIM17 stabilizes BCL2A1 by blocking TRIM28 from binding and ubiquitinating BCL2A1, and that GSK3 is involved in the phosphorylation-mediated inhibition of BCL2A1 degradation. BCL2A1 and its close relative MCL1 are thus regulated by common factors but with opposite outcome. Finally, overexpression of TRIM28 or knock-out of TRIM17 reduced BCLA1 protein levels and restored sensitivity of melanoma cells to BRAF-targeted therapy. Therefore, our data describe a molecular rheostat in which two proteins of the TRIM family antagonistically regulate BCL2A1 stability and modulate cell death.

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Section: Discussionmentioning

confidence: 99%

TRIM17 and TRIM28 antagonistically regulate the ubiquitination and anti-apoptotic activity of BCL2A1

et al. 2018

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“…Higher expression of KAP1 has been linked to prometastatic cervical cancer [114] . Moreover, the up-regulation of KAP1 could be a potential marker in colorectal cancer patients and higher level of KAP1 is correlated with poorer overall survival in patients with gastric cancer and thyroid carcinoma [115][116][117][118][119] . These clinical studies suggest that higher KAP1 level is linked to a poor prognosis in certain cancers.…”

Section: Clinical Relevance Focused On Cancer Biologymentioning

confidence: 99%

KAPtain in charge of multiple missions: Emerging roles of KAP1

Cheng

Kuo

Ann

2014

WJBC

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from conditional knockout mouse models reveal that KAP1-deficiency significantly impairs vital physiological processes, such as immune maturation, stress vulnerability, hepatic metabolism, gamete development and erythropoiesis. In this review, we summarize and evaluate current literatures involving the biochemical and physiological functions of KAP1. In addition, increasing studies on the clinical relevance of KAP1 in cancer will also be discussed. Key words: KRAB domain-associated protein 1; Transcriptional co-repressor; Post-translational modification; Chromatin remodeling; KRAB-containing zinc finger protein Core tip: This review article primarily summarizes the current findings of KAP1/TRIM28/TIF1β, with focuses on its biochemical and physiological functions. Both the canonical transcriptional co-repressor function and the transcriptional-independent roles of KAP1 are discussed in detail. We highlight the post-translational modifications and the compartmentalized localization of KAP1 and suggest that the function of KAP1 could be spatial and temporal regulated in multiple physiological circumstances. Finally, we summarize the clinical relevance of KAP1 in cancer and discuss the possibility to translate the mechanistic studies of KAP1 to human pathophysiology in the future. Abstract KAP1/TRIM28/TIF1β was identified nearly twenty years ago as a universal transcriptional co-repressor because it interacts with a large KRAB-containing zinc finger protein (KRAB-ZFP) transcription factor family. Many studies demonstrate that KAP1 affects gene expression by regulating the transcription of KRAB-ZFP-specific loci, trans-repressing as a transcriptional co-repressor or epigenetically modulating chromatin structure. Emerging evidence suggests that KAP1 also functions independent of gene regulation by serving as a SUMO/ubiquitin E3 ligase or signaling scaffold protein to mediate signal transduction. KAP1 is subjected to multiple post-translational modifications (PTMs), including serine/tyrosine phosphorylation, SUMOylation, and acetylation, which coordinately regulate KAP1 function and its protein abundance. KAP1 is involved in multiple aspects of cellular activities, including DNA damage response, virus replication, cytokine production and stem cell pluripotency. Moreover, knockout of KAP1 results in embryonic lethality, indicating that KAP1 is crucial for embryonic development and possibly impacts a wide-range of (patho)physiological manifestations. Indeed, studies World J Biol Chem 2014 August 26; 5(3): 308-320 ISSN 1949-8454 (online)

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“…Kakudo et al [16] proposed a risk stratification of thyroid follicular cell tumors based on the Ki-67 labeling index, considering high-grade histological features, such as tumor necrosis, increased mitoses, and nuclear pleomorphism, together with a high Ki-67 labeling index over 10 %, as predictors of high-risk DTC and suggested a possible risk for anaplastic transformation. The immunoreactive and cytoplasmic or nuclear apoptotic and proliferative cell markers may be helpful in the differential histological diagnosis between malignant and benign thyroid samples [27][28][29][30]. Here, we found an almost 70 % accuracy, sensitivity and specificity for Mcl-1 expression for distinguishing benign and malignant thyroid tumors.…”

Section: Correlation Ofmentioning

confidence: 52%

“…Previous reports revealed the potential benefits of combined malignancy markers such as cytokeratin 19 (CK-19), galectin-3 (Gal-3), HBME-1 (Hector Battifora Mesothelial cell), FoxP3 (Forkhead box P3), KAP-1 and mucin-1 (MUC-1) protein for routine thyroid pathology, which enhances the accuracy of the malignancy diagnosis [27][28][29][30][31]. However, further analysis is still required to evaluate the potential clinical use of these markers.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we found an almost 70 % accuracy, sensitivity and specificity for Mcl-1 expression for distinguishing benign and malignant thyroid tumors. Similarly, Martins et al [29] found a 69 % sensitivity and 75 % specificity for KAP-1 expression in the differential diagnosis of benign and malign lesions; Cunha et al [31] found 61.8 % accuracy, 62.1 % sensitivity and 61.4 % specificity for FoxP3 staining, whereas Morari et al [30] found 89 % sensitivity and 53 % specificity for MUC-1 protein expression in the histological differentiation between benign and malignant thyroid tissues. Based on these results, we suggest that Mcl-1 protein expression may help characterize PTC and could be an additional tool for routine pathological evaluation.…”

Section: Correlation Ofmentioning

confidence: 96%

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