Atypical Osteosarcomas in Werner Syndrome (Adult Progeria)

Ishikawa, Yuichi; Miller, Robert W.; Machinami, Rikuo; Sugano, Haruo; Goto, Makoto

doi:10.1111/j.1349-7006.2000.tb00924.x

Cited by 53 publications

(31 citation statements)

References 20 publications

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“…The regulation of Ku activities by Msx2 during DNA repair (55), Werner protein RecQ helicase stimulation (56,57), and telomerase targeting (58) have yet to be examined. If regulated by the osteoblast homeoproteins, these latter activities may contribute to the net actions of Msx2 on skeletal growth, osteoblast senescence, and sarcomatous transformation (59,60).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Osteocalcin Gene Expression by a Novel Ku Antigen Transcription Factor Complex

Willis¹,

Loewy²,

Charlton-Kachigian³

et al. 2002

Journal of Biological Chemistry

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We previously described an osteocalcin (OC) fibroblast growth factor (FGF) response element (FRE) DNA binding activity as a target of Msx2 transcriptional regulation. We now identify Ku70, Ku80, and Tbdn100, a variant of Tubedown-1, as constituents of the purified OCFRE-binding complex. Northern and Western blot analyses demonstrate expression of Ku and Tbdn100 in MC3T3E1 osteoblasts. FGF2 treatment regulates Ku, but not Tbdn100, protein accumulation. Gel supershift studies confirm sequence-specific DNA binding of Ku in the OCFRE complex; chromatin immunoprecipitation assays confirm association of Ku and Tbdn100 with the endogenous OC promoter. In the promoter region ؊154 to ؊113, the OCFRE is juxtaposed to OSE2, an osteoblast-specific element that binds Runx2 (Osf2, Cbfa1 (14), key features of OC promoter regulation are remarkably well conserved across mammalian species (3). The osteoblast homeoprotein Msx2 plays a crucial role in the regulation of osteoblast proliferation and differentiation (15). Msx2 and Msx1 are absolutely required for craniofacial bone formation (15). Msx2 controls the timing of osteoblast differentiation, including the temporospatial patterns of OC expression in the calvarium and teeth (12, 16). Msx2 plays a global role in determination of skeletal mass, elegantly demonstrated in murine genetic models; moreover, as highlighted by Maas and colleagues (15), osteogenic effects during development are dependent upon Msx gene dosage, suggesting that stoichiometry is an important feature of Msx2 action. Consistent with this, we (11, 12, 16 -18) and others (2, 19) have shown that Msx2 and Msx1 participate in specific protein-protein interactions that control gene transcription. In the rat OC gene, transcriptional regulation by Msx2 converges on a 42-bp region at nucleotides Ϫ154 to Ϫ113 relative to the transcription initiation site, encompassing an FGF responsive element at nucleotides Ϫ142 to Ϫ136 (17). The OCFRE (OC FGF response element) is a GCAGTCA motif that confers both basal and FGF2-regulated expression of the OC gene in MC3T3E1 calvarial osteoblasts (17,20,21). A DNA binding activity up-regulated by FGF2 in MC3T3E1 cells recognizes this element and is constitutively expressed by MG63 osteosarcoma cells (17,20). Msx2 exerts suppressive actions on the OC promoter in part by inhibiting the OCFRE DNA binding activity present in either MC3T3E1 cells or purified from MG63 cells (17). By contrast, Msx2 does not alter vitamin D receptor-dependent transcription or vitamin D receptor binding to its DNA cognate (17). Inhibition of OCFRE activity is dependent upon key regulatory domains encoded in the Msx2 homeodomain NH 2 -terminal arm and

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Section: Discussionmentioning

confidence: 99%

Regulation of Osteocalcin Gene Expression by a Novel Ku Antigen Transcription Factor Complex

Willis¹,

Loewy²,

Charlton-Kachigian³

et al. 2002

Journal of Biological Chemistry

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“…Minor signs of WS are: type 2 diabetes, hypogonadism (delayed development of secondary sexual characteristics, hypofertility, testicular or ovarian atrophy), osteoporosis, osteosclerosis of distal phalanges of fingers or toe [2], premature atherosclerosis which can cause myocardial infarction, mesenchymal tumors (sarcomas) and unusual sites of melanoma and osteosarcoma. Common carcinomas are also observed [3,4]. Abnormal voice (squeaky, acute) and flat feet are also minor signs of WS [5].…”

Section: Discussionmentioning

confidence: 99%

Werner Syndrome: A new case report

Ajili¹,

Garbouj²,

Boussetta³

et al. 2013

Our Dermatol Online

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"Werner's syndrome" or premature aging syndrome is a rare autosomal recessive genetic disease. It is responsible of several complications related to age, including atherosclerosis and association with cancer. We report the case of a 36 year-old-patient, admitted to department of Internal Medicine of the military hospital of Tunis for suspicion of systemic sclerosis. The patient had all the major signs of Werner syndrome (bilateral cataract, sclerotic skin, "bird face", baldness, small size, parental consanguinity) and 4 minor signs (type 2 diabetes, hypogonadism, squeaky voice, and flat feet). She has also a brother with the same morphotype died at the age of 32 by a myocardial infarction. The current follow-up time is 9 years.

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“…WRN has both helicase and exonuclease activities and is involved in resolving inappropriate structures during recombination, DNA replication and repair 38 . Defects in WRN are the cause of Werner syndrome, characterized by the premature onset of multiple age-related disorders, including atherosclerosis, non-insulin-dependent diabetes mellitus, ocular cataracts, osteoporosis and the appearance of rare cancers (e.g., osteosarcomas and chondrosarcomas) 39 . FANCJ (also known as BRIP1 or BACH1) is also associated with BRCA1 and is normally involved in DNA double-strand break repair by homologous recombination 40 .…”

Section: Triplex-dissociating Helicases and Cancermentioning

confidence: 99%

Triple helix-interacting proteins and cancer

M¹,

Nelson²

2013

OA Molecular Oncology

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While most naturally occurring DNA and RNA adopt the now quite familiar double-helix structure, certain sequences can under the appropriate conditions adopt a three-stranded, triplehelical structure. Both intramolecular and intermolecular triplexes have been described. Evidence for the existence of triplex structures in vivo is limited, although cellular proteins have been identified that avidly and specifically interact with such species. The postulated roles of triplexes and the proteins that interact with them in cancer and their potential utility as diagnostic markers are discussed in this review.

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Atypical Osteosarcomas in Werner Syndrome (Adult Progeria)

Cited by 53 publications

References 20 publications

Regulation of Osteocalcin Gene Expression by a Novel Ku Antigen Transcription Factor Complex

Regulation of Osteocalcin Gene Expression by a Novel Ku Antigen Transcription Factor Complex

Werner Syndrome: A new case report

Triple helix-interacting proteins and cancer

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