Crystal structure of the N-terminal domain of human CDC73 and its implications for the hyperparathyroidism-jaw tumor (HPT-JT) syndrome

Sun, Wei; Kuang, Xiaolin; Liu, Yan-Ping; Tian, Lu; Yan, Xiaozhi; Xu, Wenqing

doi:10.1038/s41598-017-15715-9

Cited by 24 publications

(32 citation statements)

References 42 publications

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“…CDC73 encodes for the tumor suppressor protein parafibromin. It downregulates cyclin D1 and cMyc expression and is required for nuclear transduction of the Wnt/β catenin signaling, playing an important role in cell proliferation, apoptosis and chromosome stability (Sun et al 2017). Inactivating CDC73 mutations are found in a large proportion of PCs, but are very rare in PAs (Howell et al 2003, Cetani et al 2004, Krebs et al 2005.…”

Section: Introductionmentioning

confidence: 99%

Gene expression profile in metastatic and non-metastatic parathyroid carcinoma

Condello

Cetani

Denaro

et al. 2021

Endocrine-Related Cancer

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Parathyroid carcinoma (PC) is one of the rarest and aggressive malignancies of the endocrine system. In some instances the histological diagnosis remains uncertain unless there is evidence of gross local invasion or secondary spread. The identification of molecular markers could improve the diagnostic accuracy of these lesions. The expression of 740 genes involved in the tumor progression processes was assessed in 8 parathyroid adenomas (PAs), 17 non-metastatic and 10 metastatic PCs using NanoString technology. Clustering analysis and Ingenuity Pathway Analysis (IPA) were interrogated to compare the gene expression profiles among the three analyzed groups and to evaluate the potential role of differentially expressed genes, respectively. The 103 differentially expressed genes between metastatic PCs and PAs are able to discriminate perfectly the two groups from a molecular point of view. The molecular signatures identified in non-metastatic PCs vs. PAs and in metastatic PCs vs. non-metastatic PCs comparisons, although with some exceptions, seem to be histotype-specific IPA reveals that hepatic fibrosis/hepatic stellate cell activation and GP6 signaling pathway are involved in malignant behavior of parathyroid tumors, whereas the activation of the HOTAIR regulatory pathway are involved in the metastatization process. Our investigation identified differentially expressed genes in non-metastatic PCs mainly encoding ECM proteins and in metastatic PCs driving endothelial-to-mesenchymal transition or encoding mediators of angiogenesis. The identified genes might be promising molecular markers potentially useful in the clinical practice for the early diagnosis and prognosis of PC.

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Section: Introductionmentioning

confidence: 99%

Gene expression profile in metastatic and non-metastatic parathyroid carcinoma

Condello

Cetani

Denaro

et al. 2021

Endocrine-Related Cancer

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“…The structures of Ras-like domain of Cdc73 38 , 39 and the Plus3 domain of RTF1 40 – 42 provide the structural basis for Paf1 complex chromatin association. Recently, the crystal structure of the N-terminal domain of CDC73 has been resolved, which may provide the molecular mechanisms of hyperparathyroidism–jaw tumor mutants 43 . The structure of histone modification domain (HMD) of Rtf1 was reported and the HMD was shown to stimulate H2B ubiquitylation through interaction with Rad6 44 .…”

Section: Introductionmentioning

confidence: 99%

Paf1 and Ctr9 subcomplex formation is essential for Paf1 complex assembly and functional regulation

et al. 2018

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The evolutionarily conserved multifunctional polymerase-associated factor 1 (Paf1) complex (Paf1C), which is composed of at least five subunits (Paf1, Leo1, Ctr9, Cdc73, and Rtf1), plays vital roles in gene regulation and has connections to development and human diseases. Here, we report two structures of each of the human and yeast Ctr9/Paf1 subcomplexes, which assemble into heterodimers with very similar conformations, revealing an interface between the tetratricopeptide repeat module in Ctr9 and Paf1. The structure of the Ctr9/Paf1 subcomplex may provide mechanistic explanations for disease-associated mutations in human PAF1 and CTR9. Our study reveals that the formation of the Ctr9/Paf1 heterodimer is required for the assembly of yeast Paf1C, and is essential for yeast viability. In addition, disruption of the interaction between Paf1 and Ctr9 greatly affects the level of histone H3 methylation in vivo. Collectively, our results shed light on Paf1C assembly and functional regulation.

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“…In NIH 3T3 cells, SHP2 tyrosine-dephosphorylase primes parafibromin to bind beta catenin, upregulate targets such as cyclin D1 and c-myc, and thereby switch parafibromin from a growth suppressor to a growth promoter (188). Most of the many N-terminal missense mutations of CDC73 are predicted to disrupt its hydrophobic N-terminal core (189,190). PAF1 may interact directly with the COMPASS complex that contains menin (191).…”

Section: Resultsmentioning

confidence: 99%

“…This is a potential tumor suppressor mechanism . Most of the many N‐terminal missense mutations of CDC73 are predicted to disrupt its hydrophobic N‐terminal core . PAF1 may interact directly with the COMPASS complex that contains menin …”

Section: Resultsmentioning

confidence: 99%

Evolution of Our Understanding of the Hyperparathyroid Syndromes: A Historical Perspective

Marx

Goltzman

2018

Journal of Bone and Mineral Research

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We review advancing and overlapping stages for our understanding of 6 hyperparathyroid (HPT) syndromes: multiple endocrine neoplasia type 1 (MEN1) or type 4, multiple endocrine neoplasia type 2A (MEN2A), hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated hyperparathyroidism. During stage 1 (1903-1967), the introduction of serum calcium measurement was a milestone that uncovered hypercalcemia as the first sign of dysfunction in many HPT subjects. Inheritability was reported in each syndrome. The earliest reports of HPT syndromes were biased towards severe or striking manifestations. During stage 2 (1959-1985), syndromes were more fully formulated. Radioimmunoassays (PTH, gastrin, insulin, prolactin, calcitonin) were breakthroughs. They could identify a syndrome carrier, indicate an emerging tumor, characterize a tumor, or monitor a tumor. During stage 3 (1981-2006), the assembly of many cases enabled recognition of further details. Age-related penetrance of a syndrome could be derived. Hormone non-secreting skin lesions were discovered in MEN1 and MEN2A. Genetic linkage could now be used for carrier detection. During stage 4 (1985 to the present), new genomic tools were a revolution for gene identification. Four principal genes (“principal” implies mutated or deleted in 50% or more probands for its syndrome) (MEN1, RET, CASR, CDC73) were identified for 5 syndromes. During stage 5 (1993 to the present), 7 syndromal genes other than a principal gene were identified (CDKN1B, CDKN2B, CDKN2C, CDKN1A, GNA11, AP2S1, GCM2). Identification of AP2S1 and GCM2 became possible because of whole exome sequencing. During stages 4 and 5, the identified genes enabled many studies, including robust detection of mutation carriers and non-carriers. Furthermore, molecular pathways of RET and the calcium-sensing receptor were elaborated, thereby facilitating developments in pharmacotherapy. Current findings hold the promise that more genes for HPT syndromes will be identified and studied in the near future.

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Crystal structure of the N-terminal domain of human CDC73 and its implications for the hyperparathyroidism-jaw tumor (HPT-JT) syndrome

Cited by 24 publications

References 42 publications

Gene expression profile in metastatic and non-metastatic parathyroid carcinoma

Gene expression profile in metastatic and non-metastatic parathyroid carcinoma

Paf1 and Ctr9 subcomplex formation is essential for Paf1 complex assembly and functional regulation

Evolution of Our Understanding of the Hyperparathyroid Syndromes: A Historical Perspective

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