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Phosphorylation-dependent and -independent functions of p130 cooperate to evoke a sustained G1 block

Hansen, Klaus; Farkas, T; Lukas, Jiri; Holm, K; Rönnstrand, Lars LU and Bartek, Jiri (2001) In EMBO Journal 20(3). p.422-432
Abstract
The retinoblastoma (pRb)-related p130 pocket protein is a regulator of cell growth and differentiation, and a candidate tumour suppressor. Both pRb and p130 operate through interactions with cellular proteins, including the E2F transcription factors. While such interactions are controlled by phosphorylation of multiple sites of pRb, regulation of p130 remains poorly understood. We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [Cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. When expressed in U2OS cells, the phosphorylation-deficient mutant p130(Delta)(CDK4), in which the Cdk4... (More)
The retinoblastoma (pRb)-related p130 pocket protein is a regulator of cell growth and differentiation, and a candidate tumour suppressor. Both pRb and p130 operate through interactions with cellular proteins, including the E2F transcription factors. While such interactions are controlled by phosphorylation of multiple sites of pRb, regulation of p130 remains poorly understood. We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [Cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. When expressed in U2OS cells, the phosphorylation-deficient mutant p130(Delta)(CDK4), in which the Cdk4 specific sites were mutated to alanine residues, imposed a more sustained G1 arrest than a constitutively active pRb(Delta)(CDK), known to repress all cellular E2F activity. Experiments using p130(Delta)(Cdk4) and another phosphorylation-deficient mutant, p130(PM19A), with 19 phosphorylation sites mutated, revealed that the p130-imposed G1 block reflects cooperative growth-suppressive effects of phosphorylation-regulated E2F binding and phosphorylation-independent sequestration of cyclin E(A)-Cdk2 through the N-terminal cyclin binding motif of p130. (Less)
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author
publishing date
type
Contribution to journal
publication status
published
subject
in
EMBO Journal
volume
20
issue
3
pages
422 - 432
publisher
Oxford University Press
external identifiers
  • Scopus:0035254222
ISSN
1460-2075
language
English
LU publication?
no
id
8d6362e9-91ec-4cde-a8ea-503ea6f9c69f (old id 1782453)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/11157749
http://www.nature.com/emboj/journal/v20/n3/full/7593549a.html
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC133464/
date added to LUP
2013-05-14 16:09:35
date last changed
2016-10-13 04:24:20
@misc{8d6362e9-91ec-4cde-a8ea-503ea6f9c69f,
  abstract     = {The retinoblastoma (pRb)-related p130 pocket protein is a regulator of cell growth and differentiation, and a candidate tumour suppressor. Both pRb and p130 operate through interactions with cellular proteins, including the E2F transcription factors. While such interactions are controlled by phosphorylation of multiple sites of pRb, regulation of p130 remains poorly understood. We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [Cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. When expressed in U2OS cells, the phosphorylation-deficient mutant p130(Delta)(CDK4), in which the Cdk4 specific sites were mutated to alanine residues, imposed a more sustained G1 arrest than a constitutively active pRb(Delta)(CDK), known to repress all cellular E2F activity. Experiments using p130(Delta)(Cdk4) and another phosphorylation-deficient mutant, p130(PM19A), with 19 phosphorylation sites mutated, revealed that the p130-imposed G1 block reflects cooperative growth-suppressive effects of phosphorylation-regulated E2F binding and phosphorylation-independent sequestration of cyclin E(A)-Cdk2 through the N-terminal cyclin binding motif of p130.},
  author       = {Hansen, Klaus and Farkas, T and Lukas, Jiri and Holm, K and Rönnstrand, Lars and Bartek, Jiri},
  issn         = {1460-2075},
  language     = {eng},
  number       = {3},
  pages        = {422--432},
  publisher    = {ARRAY(0x993b558)},
  series       = {EMBO Journal},
  title        = {Phosphorylation-dependent and -independent functions of p130 cooperate to evoke a sustained G1 block},
  volume       = {20},
  year         = {2001},
}