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TGF-beta enforces s...
TGF-beta enforces senescence in Myc-transformed hematopoietic tumor cells through induction of Mad1 and repression of Myc activity
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- Wu, Siqin (författare)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för växtbiologi,Department of Plant Biology
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- Hultquist, Anne (författare)
- Uppsala universitet,Institutionen för genetik och patologi
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- Hydbring, Per (författare)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Karolinska Institutet,Institutionen för växtbiologi,Department of Plant Biology,Karolinska Institute
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- Cetinkaya, Cihan (författare)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Uppsala universitet,Institutionen för genetik och patologi,Institutionen för växtbiologi,Department of Plant Biology,Uppsala University
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- Öberg, Fredrik (författare)
- Uppsala universitet,Institutionen för genetik och patologi
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- Larsson, Lars-Gunnar (författare)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Karolinska Institutet,Institutionen för växtbiologi,Department of Plant Biology,Karolinska Institute
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(creator_code:org_t)
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- Elsevier BV, 2009
- 2009
- Engelska.
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 315:18, s. 3099-3111
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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https://res.slu.se/i...
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Abstract
Ämnesord
Stäng
- Inhibition of tumor growth factor (TGF)-beta-mediated cell cycle exit is considered an important tumorigenic function of Myc oncoproteins. Here we found that TGF-beta1 enforced G(1) cell cycle arrest and cellular senescence in human U-937 myeloid tumor cells ectopically expressing v-Myc, which contains a stabilizing mutation frequently found in lymphomas. This correlated with induced expression of the Myc antagonist Mad1, resulting in replacement of Myc for Mad1 at target promoters, reduced histone acetylation and strong repression of Myc-driven transcription. The latter was partially reversed by histone deacetylase (HDAC) inhibitors, consistent with involvement of Mad1. Importantly, knockdown of MAD1 expression prevented TGF-beta1-induced senescence, underscoring that Mad1 is a crucial component of this process. Enforced Mad1 expression sensitized U-937-myc cells to TGF-beta and restored phorbol ester-induced cell cycle exit, but could not alone induce G(1) arrest, suggesting that Mad1 is required but not sufficient for cellular senescence. Our results thus demonstrate that TGF-beta can override Myc activity despite a stabilizing cancer mutation and induce senescence in myeloid tumor cells, at least in part by induction of Mad1. TGF-beta-induced senescence, or signals mimicking this pathway, could therefore potentially be explored as a therapeutic principle for treating hematopoietic and other tumors with deregulated MYC expression.
Ämnesord
- LANTBRUKSVETENSKAPER -- Lantbruksvetenskap, skogsbruk och fiske -- Livsmedelsvetenskap (hsv//swe)
- AGRICULTURAL SCIENCES -- Agriculture, Forestry and Fisheries -- Food Science (hsv//eng)
- LANTBRUKSVETENSKAPER -- Husdjursvetenskap (hsv//swe)
- AGRICULTURAL SCIENCES -- Animal and Dairy Sience (hsv//eng)
- LANTBRUKSVETENSKAPER -- Veterinärmedicin (hsv//swe)
- AGRICULTURAL SCIENCES -- Veterinary Science (hsv//eng)
Nyckelord
- Myc
- Mad
- TGF-beta
- Senescence
- Cell cycle
- Cancer
- MEDICINE
- MEDICIN
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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