Proteasomal activity modulates TGF‐ß signaling in a gene‐specific manner

Zhang, Fan; Mönkkönen, Mia; Roth, Stephan; Laiho, Marikki

doi:10.1016/s0014-5793(02)03163-0

Cited by 15 publications

(7 citation statements)

References 32 publications

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“…Rather, SnoN acts in a gene-specific manner, and inhibition of the proteasome leads to abrogation of certain TGF␤1 target gene regulation, without any effect on other TGF␤1 target genes (49). Furthermore, recent reports indicate that under certain circumstances SnoN can act as a positive The translation initiation site is at nucleotide position ϩ1, the putative transcription start site (TSS) is located at position Ϫ220, the 5Ј-untranslated region is shown in black, the genomic upstream sequence is in gray, the 9ϫGTCT repeat at Ϫ1368 to Ϫ1333 is indicated by the asterisk, the activin response element at Ϫ2685 to Ϫ2678 is indicated by the circle.…”

Section: Discussionmentioning

confidence: 99%

The Role of SnoN in Transforming Growth Factor β1-induced Expression of Metalloprotease-Disintegrin ADAM12

Solomon

Muggy

et al. 2010

Journal of Biological Chemistry

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Increased expression of metalloprotease-disintegrin ADAM12 is a hallmark of several pathological conditions, including cancer, cardiovascular disease, and certain inflammatory diseases of the central nervous system or the muscoskeletal system. We show that transforming growth factor ␤1 (TGF␤1) is a potent inducer of ADAM12 mRNA and protein in mouse fibroblasts and in mouse and human mammary epithelial cells. Induction of ADAM12 is detected within 2 h of treatment with TGF␤1, is Smad2/Smad3-dependent, and is a result of derepression of the ADAM12, a member of the metalloprotease-disintegrin family of proteins, has been implicated in the progression of cancer, cardiovascular disease, osteoarthritis, and neurological disorders (1). The ADAM12 gene is frequently mutated in human breast cancers (2, 3), and cancer-associated mutations cause mislocalization of the ADAM12 protein in cells and alter its function (4). Missense single nuclear polymorphism in the ADAM12 gene shows strong association with osteoarthritis (5, 6). In addition to changes in its amino acid sequence, expression levels of ADAM12 are significantly increased in many pathological states. For example, ADAM12 expression levels are 20 -30-fold higher in human breast tumors than in normal mammary epithelium (7-12). ADAM12 expression is also markedly up-regulated in cancers of the liver, lung, stomach, colon, prostate, bladder, and in glioblastoma (13-18). Increased ADAM12 expression levels are found in the cardiac tissue of patients with hypertrophic obstructive cardiomyopathy (19) and in mice with angiotensin II-induced hypertension and cardiac hypertrophy (20,21). During inflammatory responses and aseptic osteolysis associated with loosened hip replacement implants, ADAM12 is up-regulated in the interface tissue around loosening implants (22). In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, ADAM12 level is markedly increased in the T cells that infiltrate spinal cords (23).The mechanisms regulating ADAM12 expression, in particular those that may be responsible for altered levels of ADAM12 in various pathological states, are poorly understood. Previous studies employing hepatic stellate cells, a mesenchymal cell type in hepatic parenchyma, have indicated that ADAM12 expression is induced by transforming growth factor ␤ (TGF␤) 2 (13, 24). The TGF␤ signaling pathway is initiated when one of the family members, e.g. TGF␤1, -␤2, or -␤3, binds to a complex of TGF␤ type I and type II serine/threonine kinase receptors (T␤RI and T␤RII, respectively) and induces phosphorylation and activation of T␤RI by T␤RII. T␤RI then phosphorylates receptor Smads (R-Smads), Smad2 and Smad3. Phosphorylated Smad2/3 associate with the common partner Smad4 and translocate to the nucleus, where they regulate transcription of target genes (25,26). In addition, receptor activation in certain cell types leads to Smad-independent responses via the activation of mitogen-activated protein kinases (MAPKs), phosphoinositide 3-kinase, and Rho family memb...

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Section: Discussionmentioning

confidence: 99%

The Role of SnoN in Transforming Growth Factor β1-induced Expression of Metalloprotease-Disintegrin ADAM12

Solomon

Muggy

et al. 2010

Journal of Biological Chemistry

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“…Tight control of the level and activity of Smad is critical for TGF‐β to function properly 18 . Recently, several key transducers in the TGF‐β signalling pathway have been recognized as being affected by the ubiquitin–proteasome system 19 . Destruction of R‐Smad, Smad2 and 3, is dependent on a proteasome pathway 20 .…”

Section: Discussionmentioning

confidence: 99%

“…18 Recently, several key transducers in the TGF-b signalling pathway have been recognized as being affected by the ubiquitin-proteasome system. 19 Destruction of R-Smad, Smad2 and 3, is dependent on a proteasome pathway. 20 Conversely, inhibitory Smad7 is also a target of proteasomal degradation.…”

Section: Discussionmentioning

confidence: 99%

Effects of proteasome inhibitors on rat renal fibrosis in vitro and in vivo

et al. 2010

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“…HeLa cells were transfected by lipofection with cyclin E-pRC-cytomegalovirus expression vector, incubated for 24 h, fixed, and stained for cyclin E as described by Zhang et al (2002).…”

Section: Mice Mouse Strains Deficient For P19mentioning

confidence: 99%

p19^Ink4dand p21^Cip1Collaborate to Maintain the Postmitotic State of Auditory Hair Cells, Their Codeletion Leading to DNA Damage and p53-Mediated Apoptosis

Laine¹,

Doetzlhofer²,

Mantela³

et al. 2007

J. Neurosci.

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Sensory hair cells of the auditory organ are generated during embryogenesis and remain postmitotic throughout life. Previous work has shown that inactivation of the cyclin-dependent kinase inhibitor (CKI) p19Ink4d leads to progressive hearing loss attributable to inappropriate DNA replication and subsequent apoptosis of hair cells. Here we show the synergistic action of another CKI, p21 Cip1 , on cell cycle reactivation. The codeletion of p19Ink4d and p21 Cip1 triggered profuse S-phase entry of auditory hair cells during a restricted period in early postnatal life, leading to the transient appearance of supernumerary hair cells. In addition, we show that aberrant cell cycle reentry leads to activation of a DNA damage response pathway in these cells, followed by p53-mediated apoptosis. The majority of hair cells were absent in adult cochleas. These data, together with the demonstration of changing expression patterns of multiple CKIs in auditory hair cells during the stages of early postnatal maturation, show that the maintenance of the postmitotic state is an active, tissue-specific process, cooperatively regulated by several CKIs, and is critical for the lifelong survival of these sensory cells.

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Proteasomal activity modulates TGF‐ß signaling in a gene‐specific manner

Cited by 15 publications

References 32 publications

The Role of SnoN in Transforming Growth Factor β1-induced Expression of Metalloprotease-Disintegrin ADAM12

The Role of SnoN in Transforming Growth Factor β1-induced Expression of Metalloprotease-Disintegrin ADAM12

Effects of proteasome inhibitors on rat renal fibrosis in vitro and in vivo

p19^Ink4dand p21^Cip1Collaborate to Maintain the Postmitotic State of Auditory Hair Cells, Their Codeletion Leading to DNA Damage and p53-Mediated Apoptosis

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Proteasomal activity modulates TGF‐ß signaling in a gene‐specific manner

Cited by 15 publications

References 32 publications

The Role of SnoN in Transforming Growth Factor β1-induced Expression of Metalloprotease-Disintegrin ADAM12

The Role of SnoN in Transforming Growth Factor β1-induced Expression of Metalloprotease-Disintegrin ADAM12

Effects of proteasome inhibitors on rat renal fibrosis in vitro and in vivo

p19Ink4dand p21Cip1Collaborate to Maintain the Postmitotic State of Auditory Hair Cells, Their Codeletion Leading to DNA Damage and p53-Mediated Apoptosis

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p19^Ink4dand p21^Cip1Collaborate to Maintain the Postmitotic State of Auditory Hair Cells, Their Codeletion Leading to DNA Damage and p53-Mediated Apoptosis