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Attisano, Liliana; Lee-Hoeflich, Si Tuen

doi:10.1186/gb-2001-2-8-reviews3010

Cited by 151 publications

(112 citation statements)

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“…The presence of multiple congenital malformations correlates with the expression profile of SMAD4, which is ubiquitously expressed throughout the embryonic development and in most adult tissue and cell types. 21 Notably conditional knockout of Smad4 in mouse chondrocytes leads to dwarfism, with histological anomalies of the growth plates, 22 associated with a sensorineural hearing loss due to abnormalities of the cochlea in size and histology. 23 However, skeletal features were not consistently observed in our cohort, although brachydactyly, thick calvarium and large pedicles were frequent.…”

Section: Discussionmentioning

confidence: 99%

Myhre and LAPS syndromes: clinical and molecular review of 32 patients

et al. 2014

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Myhre syndrome is characterized by short stature, brachydactyly, facial features, pseudomuscular hypertrophy, joint limitation and hearing loss. We identified SMAD4 mutations as the cause of Myhre syndrome. SMAD4 mutations have also been identified in laryngotracheal stenosis, arthropathy, prognathism and short stature syndrome (LAPS). This study aimed to review the features of Myhre and LAPS patients to define the clinical spectrum of SMAD4 mutations. We included 17 females and 15 males ranging in age from 8 to 48 years. Thirty were diagnosed with Myhre syndrome and two with LAPS. SMAD4 coding sequence was analyzed by Sanger sequencing. Clinical and radiological features were collected from a questionnaire completed by the referring physicians. All patients displayed a typical facial gestalt, thickened skin, joint limitation and muscular pseudohypertrophy. Growth retardation was common (68.7%) and was variable in severity (from À5.5 to À2 SD), as was mild-to-moderate intellectual deficiency (87.5%) with additional behavioral problems in 56.2% of the patients. Significant health concerns like obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis, pericarditis and early death occurred in four. Twenty-nine patients had a de novo heterozygous SMAD4 mutation, including both patients with LAPS. In 27 cases mutation affected Ile500 and in two cases Arg496. The three patients without SMAD4 mutations had typical findings of Myhre syndrome. Myhre-LAPS syndrome is a clinically homogenous condition with life threatening complications in the course of the disease. Our identification of SMAD4 mutations in 29/32 cases confirms that SMAD4 is the major gene responsible for Myhre syndrome.

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Section: Discussionmentioning

confidence: 99%

Myhre and LAPS syndromes: clinical and molecular review of 32 patients

et al. 2014

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“…This topic has been extensively reviewed (Massague and Chen, 2000;Attisano et al, 2001;Derynck et al, 2001;Moustakas et al, 2001;Piek and Roberts, 2001;Rooke and Crosier, 2001;Wong and Lai, 2001;ten Dijke et al, 2002;Verrecchia and Mauviel, 2002), therefore, I will only highlight some important findings and focus on SKI overexpression, and its consequences for TGF-b signaling, and melanoma tumor progression. TGF-b functions as a negative growth regulator for epithelial cells from diverse tissues, but it is also a potent growth promoter for mesenchymal, smooth muscle cells, and chondrocytes.…”

Section: C-ski Is a Potent Repressor Of Tgf-b Signalingmentioning

confidence: 99%

Repression of TGF-β signaling by the oncogenic protein SKI in human melanomas: consequences for proliferation, survival, and metastasis

Medrano

2003

Oncogene

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Transforming growth factor-b (TGF-b) has dual and paradoxical functions as a tumor suppressor and promoter of tumor progression and metastasis. TGF-b-mediated growth inhibition is gradually lost during melanoma tumor progression, but there are no measurable defects at the receptor level. Furthermore, melanoma cells release high levels of TGF-b to the microenvironment, which upon activation induces matrix deposition, angiogenesis, survival, and transition to more aggressive phenotypes. The SKI and SnoN protein family associate with and repress the activity of Smad2, Smad3, and Smad4, three members of the TGF-b signaling pathway. SKI also facilitates cellcycle progression by targeting the RB pathway by at least two ways: it directly associates with RB and represses its activity when expressed at high levels, and indirectly, it represses Smad-mediated induction of p21 Waf-1 . This results in increased CDK2 activity, RB phosphorylation, and inactivation. Therefore, high levels of SKI result in lesions to the RB pathway in a manner similar to p16 INK4a loss. SKI mRNA and protein levels dramatically increase during human melanoma tumor progression. In addition, the SKI protein shifts from nuclear localization in intraepidermal melanoma cells to nuclear and cytoplasmic in invasive and metastatic melanomas. Here, I discuss the basis for repression of intracellular TGF-b signaling by SKI, some additional activities of this protein, and propose that by disrupting multiple tumor suppressor pathways, SKI functions as a melanoma oncogene.

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“…Furthermore, hepatic expression of mature TGF-b1 in transgenic mice resulted in multiple tissue lesions, including hepatic fibrosis and apoptotic death of hepatocytes (Sanderson et al, 1995). TGF-b1 can signal through intracellular mediators known as Smads, which are localized in the cytoplasm (Attisano and Tuen Lee-Hoeflich, 2001). Following TGF-b1 receptor-mediated phosphorylation, Smad2 and 3 associate as heteromeric complexes with the common signaling mediator Smad4 and translocate into the nucleus to regulate gene expression.…”

Section: Introductionmentioning

confidence: 99%