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PRKAR1A inactivation leads to increased proliferation and decreased apoptosis in human B lymphocytes

Robinson-White, Audrey J. ; Leitner, Wolfgang W. ; Aleem, Eiman ; Kaldis, Philipp LU orcid ; Bossis, Ioannis and Stratakis, Constantine A. (2006) In Cancer Research 66(21). p.10603-10612
Abstract

The multiple neoplasia syndrome Carney complex (CNC) is caused by heterozygote mutations in the gene, which codes for the RIα regulatory subunit (PRKAR1A) of protein kinase A. Inactivation of PRKAR1A and the additional loss of the normal allele lead to tumors in CNC patients and increased cyclic AMP signaling in their cells, but the oncogenetic mechanisms in affected tissues remain unknown. Previous studies suggested that PRKAR1A down-regulation may lead to increased mitogen-activated protein kinase (MAPK) signaling. Here, we show that, in lymphocytes with PRKAR1A-inactivating mutations, there is increased extracellular signal-regulated kinase (ERK) 1/2 and B-raf phosphorylation and MAPK/ERK kinase 1/2 and c-Myc activation, whereas... (More)

The multiple neoplasia syndrome Carney complex (CNC) is caused by heterozygote mutations in the gene, which codes for the RIα regulatory subunit (PRKAR1A) of protein kinase A. Inactivation of PRKAR1A and the additional loss of the normal allele lead to tumors in CNC patients and increased cyclic AMP signaling in their cells, but the oncogenetic mechanisms in affected tissues remain unknown. Previous studies suggested that PRKAR1A down-regulation may lead to increased mitogen-activated protein kinase (MAPK) signaling. Here, we show that, in lymphocytes with PRKAR1A-inactivating mutations, there is increased extracellular signal-regulated kinase (ERK) 1/2 and B-raf phosphorylation and MAPK/ERK kinase 1/2 and c-Myc activation, whereas c-Raf-1 is inhibited. These changes are accompanied by increased cell cycle rates and decreased apoptosis that result in an overall net gain in proliferation and survival. In conclusion, inactivation of PRKAR1A leads to widespread changes in molecular pathways that control cell cycle and apoptosis. This is the first study to show that human cells with partially inactivated RIα levels have increased proliferation and survival, suggesting that loss of the normal allele in these cells is not necessary for these changes to occur.

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author
; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
in
Cancer Research
volume
66
issue
21
pages
10603 - 10612
publisher
American Association for Cancer Research Inc.
external identifiers
  • scopus:33751301602
  • pmid:17079485
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-06-2200
language
English
LU publication?
no
id
fc1bd19f-2119-4dd0-aea5-c09ded62dd25
date added to LUP
2019-09-18 14:20:36
date last changed
2024-05-29 00:56:22
@article{fc1bd19f-2119-4dd0-aea5-c09ded62dd25,
  abstract     = {{<p>The multiple neoplasia syndrome Carney complex (CNC) is caused by heterozygote mutations in the gene, which codes for the RIα regulatory subunit (PRKAR1A) of protein kinase A. Inactivation of PRKAR1A and the additional loss of the normal allele lead to tumors in CNC patients and increased cyclic AMP signaling in their cells, but the oncogenetic mechanisms in affected tissues remain unknown. Previous studies suggested that PRKAR1A down-regulation may lead to increased mitogen-activated protein kinase (MAPK) signaling. Here, we show that, in lymphocytes with PRKAR1A-inactivating mutations, there is increased extracellular signal-regulated kinase (ERK) 1/2 and B-raf phosphorylation and MAPK/ERK kinase 1/2 and c-Myc activation, whereas c-Raf-1 is inhibited. These changes are accompanied by increased cell cycle rates and decreased apoptosis that result in an overall net gain in proliferation and survival. In conclusion, inactivation of PRKAR1A leads to widespread changes in molecular pathways that control cell cycle and apoptosis. This is the first study to show that human cells with partially inactivated RIα levels have increased proliferation and survival, suggesting that loss of the normal allele in these cells is not necessary for these changes to occur.</p>}},
  author       = {{Robinson-White, Audrey J. and Leitner, Wolfgang W. and Aleem, Eiman and Kaldis, Philipp and Bossis, Ioannis and Stratakis, Constantine A.}},
  issn         = {{0008-5472}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{21}},
  pages        = {{10603--10612}},
  publisher    = {{American Association for Cancer Research Inc.}},
  series       = {{Cancer Research}},
  title        = {{PRKAR1A inactivation leads to increased proliferation and decreased apoptosis in human B lymphocytes}},
  url          = {{http://dx.doi.org/10.1158/0008-5472.CAN-06-2200}},
  doi          = {{10.1158/0008-5472.CAN-06-2200}},
  volume       = {{66}},
  year         = {{2006}},
}