Jun activation domain-binding protein 1 expression in breast cancer inversely correlates with the cell cycle inhibitor p27(Kip1).

The Jun activation domain-binding protein 1 (JAB1), aside from being an activator protein 1 coactivator, is involved in degradation of the cyclin-dependent kinase inhibitor p27. We examined JAB1 and p27 protein expression in invasive breast carcinoma specimens and the association of this expression with clinical outcome. JAB1 was detected immunohistochemically in 43 of 53 (81%) tumors; 32 (60%) breast carcinomas showed high JAB1 expression (>50% of cells positive) and reduced or absent p27 levels (P = 0.02, Mann-Whitney U test). Tumors with high p27 expression were rarely positive for JAB1. All eight patients with JAB1-negative tumors had no evidence of relapse or disease progression at a median follow-up of 70 months. Immunoblotting showed strong JAB1 expression in breast carcinoma samples but not in paired normal breast epithelial samples. Targeted overexpression of JAB1 by regulated adenovirus in breast cancer cell lines also reduced p27 levels by accelerating degradation of p27. Thus, the JAB1:p27 ratio may be a novel indicator of aggressive, high-grade tumor behavior, and control of JAB1 could be a novel target for experimental therapies.

[1]  M. Korbonits,et al.  Expression of phosphorylated p27(Kip1) protein and Jun activation domain-binding protein 1 in human pituitary tumors. , 2002, The Journal of clinical endocrinology and metabolism.

[2]  C. Markopoulos,et al.  High expression levels of p27 correlate with lymph node status in a subset of advanced invasive breast carcinomas , 2002, Cancer.

[3]  C. J. Barnes,et al.  Heregulin induces expression, ATPase activity, and nuclear localization of G3BP, a Ras signaling component, in human breast tumors. , 2002, Cancer research.

[4]  Xuesong Cao,et al.  Jab1 antagonizes TGF‐β signaling by inducing Smad4 degradation , 2002 .

[5]  Minoru Yoshida,et al.  The Cytoplasmic Shuttling and Subsequent Degradation of p27Kip1 Mediated by Jab1/CSN5 and the COP9 Signalosome Complex* , 2002, The Journal of Biological Chemistry.

[6]  Y. M. Lee,et al.  Jab1 Interacts Directly with HIF-1α and Regulates Its Stability* , 2002, The Journal of Biological Chemistry.

[7]  F. He,et al.  Intracrine hepatopoietin potentiates AP‐1 activity through JAB1 independent of MAPK pathway , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  Y. Dong,et al.  Jab1 expression is associated with inverse expression of p27(kip1) and poor prognosis in epithelial ovarian tumors. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[9]  C. Schwechheimer,et al.  COP9 signalosome revisited: a novel mediator of protein degradation. , 2001, Trends in cell biology.

[10]  James M. Roberts,et al.  A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase , 2001, Nature.

[11]  D. Chamovitz,et al.  JAB1/CSN5 and the COP9 signalosome , 2001, EMBO reports.

[12]  J. Bernhagen,et al.  Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1 , 2000, Nature.

[13]  J. Winnie,et al.  Transcriptional regulation of cell invasion: AP-1 regulation of a multigenic invasion programme. , 2000, European journal of cancer.

[14]  R. Pardi,et al.  Integrin LFA-1 interacts with the transcriptional co-activator JAB1 to modulate AP-1 activity , 2000, Nature.

[15]  I. Ellis,et al.  Biological and clinical associations of c‐jun activation in human breast cancer , 2000, International journal of cancer.

[16]  P. Brown,et al.  cJun overexpression in MCF-7 breast cancer cells produces a tumorigenic, invasive and hormone resistant phenotype , 1999, Oncogene.

[17]  M. Piris,et al.  Anomalous high p27/KIP1 expression in a subset of aggressive B-cell lymphomas is associated with cyclin D3 overexpression. p27/KIP1-cyclin D3 colocalization in tumor cells. , 1999, Blood.

[18]  James M. Roberts,et al.  CDK inhibitors: positive and negative regulators of G1-phase progression. , 1999, Genes & development.

[19]  Andrea C. Carrano,et al.  Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation. , 1999, Genes & development.

[20]  J. Kato,et al.  Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1 , 1999, Nature.

[21]  R. Kraft,et al.  A novel protein complex involved in signal transduction possessing similarities to 26S proteasome subunits , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  Bruno Amati,et al.  Phosphorylation‐dependent degradation of the cyclin‐dependent kinase inhibitor p27Kip1 , 1997, The EMBO journal.

[23]  James M. Roberts,et al.  Cyclin E-CDK2 is a regulator of p27Kip1. , 1997, Genes & development.

[24]  Herman Yeger,et al.  Decreased levels of the cell-cycle inhibitor p27Kip1 protein: Prognostic implications in primary breast cancer , 1997, Nature Medicine.

[25]  T. Toda,et al.  A new group of conserved coactivators that increase the specificity of AP-1 transcription factors , 1996, Nature.

[26]  P. Beer-Romero,et al.  Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. , 1995, Science.

[27]  James M. Roberts,et al.  Cloning of p27 Kip1 , a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals , 1994, Cell.

[28]  D. Chamovitz.  A complex situation , 2001 .