| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 275, Issue 50, 39223-39230, December 15, 2000
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the Deregulation of cell cycle checkpoints is an
almost universal abnormality in human cancers and is most often due to
loss-of-function mutations of tumor suppressor genes such as Rb, p53,
or p16INK4a. In this study, we demonstrate that
BCR/ABL inhibits the expression of a key cell cycle inhibitor,
p27Kip1, by signaling through a pathway involving
phosphatidylinositol 3-kinase (PI3K). p27Kip1 is a widely
expressed inhibitor of cdk2, an essential cell cycle kinase regulating
entry into S phase. We demonstrate that the decrease of
p27Kip1 is directly due to BCR/ABL in hematopoietic cells
by two different approaches. First, induction of BCR/ABL by a
tetracycline-regulated promoter is associated with a reversible
down-regulation of p27Kip1. Second, inhibition of BCR/ABL
kinase activity with the Abl tyrosine kinase inhibitor STI571 rapidly
increases p27Kip1 levels. The PI3K inhibitor LY-294002
blocks the ability of BCR/ABL to induce p27Kip1
down-regulation and inhibits BCR/ABL-induced entry into S phase. The
serine/threonine kinase AKT/protein kinase B is a known
downstream target of PI3K. Transient expression of an activated mutant
of AKT was found to decrease expression of p27Kip1, even
when PI3K was inhibited by LY-294002. The mechanism of p27Kip1 regulation is primarily related to protein
stability, since inhibition of proteasome activity increased
p27Kip1 levels in BCR/ABL-transformed cells, whereas very
little change in p27 transcription was found. Overall, these data are
consistent with a model in which BCR/ABL suppresses p27Kip1
protein levels through PI3K/AKT, leading to accelerated entry into S
phase. This activity is likely to explain in part previous studies
showing that activation of PI3K was required for optimum transformation
of hematopoietic cells by BCR/ABL in vitro and in
vivo.
BCR/ABL Regulates Expression of the Cyclin-dependent
Kinase Inhibitor p27Kip1 through the Phosphatidylinositol
3-Kinase/AKT Pathway*
§,§,¶,¶, and§
Department of Adult Oncology, Dana Farber
Cancer Institute and Departments of § Medicine and
¶ Pathology, Brigham and Women's Hospital and Harvard Medical
School, Boston, Massachusetts, 02115
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dana Farber Cancer
Institute, Dept. of Adult Oncology, 44 Binney St., Boston MA 02115. Tel.: 617-632-3360; Fax: 617-632-4388; E-mail:
james_griffin@dfci.harvard.edu.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  B. Li, A. Sun, H. Youn, Y. Hong, P. F. Terranova, J.B. Thrasher, P. Xu, and D. Spencer Conditional Akt activation promotes androgen-independent progression of prostate cancer Carcinogenesis, March 1, 2007; 28(3): 572 - 583. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. U. Birkenkamp, A. Essafi, K. E. van der Vos, M. da Costa, R. C.-Y. Hui, F. Holstege, L. Koenderman, E. W.-F. Lam, and P. J. Coffer FOXO3a Induces Differentiation of Bcr-Abl-transformed Cells through Transcriptional Down-regulation of Id1 J. Biol. Chem., January 26, 2007; 282(4): 2211 - 2220. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kometani, M. Aoki, S. Kawamata, Y. Shinozuka, T. Era, M. Taniwaki, M. Hattori, and N. Minato Role of SPA-1 in Phenotypes of Chronic Myelogenous Leukemia Induced by BCR-ABL-Expressing Hematopoietic Progenitors in a Mouse Model. Cancer Res., October 15, 2006; 66(20): 9967 - 9976. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. Jacobsen, O. Ananieva, M. L. Brown, and Y. Chang Growth, Differentiation, and Malignant Transformation of Pre-B Cells Mediated by Inducible Activation of v-Abl Oncogene. J. Immunol., June 1, 2006; 176(11): 6831 - 6838. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ohta, M. Ohmichi, T. Hayasaka, S. Mabuchi, M. Saitoh, J. Kawagoe, K. Takahashi, H. Igarashi, B. Du, M. Doshida, et al. Inhibition of Phosphatidylinositol 3-Kinase Increases Efficacy of Cisplatin in in Vivo Ovarian Cancer Models Endocrinology, April 1, 2006; 147(4): 1761 - 1769. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Parmar, J. Smith, A. Sassano, S. Uddin, E. Katsoulidis, B. Majchrzak, S. Kambhampati, E. A. Eklund, M. S. Tallman, E. N. Fish, et al. Differential regulation of the p70 S6 kinase pathway by interferon {alpha} (IFN{alpha}) and imatinib mesylate (STI571) in chronic myelogenous leukemia cells Blood, October 1, 2005; 106(7): 2436 - 2443. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-y. Ren, E. Bolton, M. G. Mohi, A. Morrione, B. G. Neel, and T. Skorski Phosphatidylinositol 3-Kinase p85{alpha} Subunit-Dependent Interaction with BCR/ABL-Related Fusion Tyrosine Kinases: Molecular Mechanisms and Biological Consequences Mol. Cell. Biol., September 15, 2005; 25(18): 8001 - 8008. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. B. Dickerson, R. Thomas, S. P. Fosmire, A. R. Lamerato-Kozicki, S. R. Bianco, J. W. Wojcieszyn, M. Breen, S. C. Helfand, and J. F. Modiano Mutations of Phosphatase and Tensin Homolog Deleted from Chromosome 10 in Canine Hemangiosarcoma Vet. Pathol., September 1, 2005; 42(5): 618 - 632. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Sakakibara, K. Kubota, B. Worku, E. J. Ryer, J. P. Miller, A. Koff, K. C. Kent, and B. Liu PDGF-BB Regulates p27 Expression through ERK-dependent RNA Turn-over in Vascular Smooth Muscle Cells J. Biol. Chem., July 8, 2005; 280(27): 25470 - 25477. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Andreu, E. Lledo, E. Poch, C. Ivorra, M. P. Albero, J. A. Martinez-Climent, C. Montiel-Duarte, J. Rifon, J. Perez-Calvo, C. Arbona, et al. BCR-ABL Induces the Expression of Skp2 through the PI3K Pathway to Promote p27Kip1 Degradation and Proliferation of Chronic Myelogenous Leukemia Cells Cancer Res., April 15, 2005; 65(8): 3264 - 3272. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Motti, D. Califano, G. Troncone, C. De Marco, I. Migliaccio, E. Palmieri, L. Pezzullo, L. Palombini, A. Fusco, and G. Viglietto Complex Regulation of the Cyclin-Dependent Kinase Inhibitor p27kip1 in Thyroid Cancer Cells by the PI3K/AKT Pathway: Regulation of p27kip1 Expression and Localization Am. J. Pathol., March 1, 2005; 166(3): 737 - 749. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tomoda, J.-y. Kato, E. Tatsumi, T. Takahashi, Y. Matsuo, and N. Yoneda-Kato The Jab1/COP9 signalosome subcomplex is a downstream mediator of Bcr-Abl kinase activity and facilitates cell-cycle progression Blood, January 15, 2005; 105(2): 775 - 783. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Mabuchi, M. Ohmichi, Y. Nishio, T. Hayasaka, A. Kimura, T. Ohta, J. Kawagoe, K. Takahashi, N. Yada-Hashimoto, H. Seino-Noda, et al. Inhibition of Inhibitor of Nuclear Factor-{kappa}B Phosphorylation Increases the Efficacy of Paclitaxel in in Vitro and in Vivo Ovarian Cancer Models Clin. Cancer Res., November 15, 2004; 10(22): 7645 - 7654. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H Eguchi, S Carpentier, S S Kim, and S F Moss p27kip1 regulates the apoptotic response of gastric epithelial cells to Helicobacter pylori Gut, June 1, 2004; 53(6): 797 - 804. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Calabretta and D. Perrotti The biology of CML blast crisis Blood, June 1, 2004; 103(11): 4010 - 4022. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mabuchi, M. Ohmichi, Y. Nishio, T. Hayasaka, A. Kimura, T. Ohta, M. Saito, J. Kawagoe, K. Takahashi, N. Yada-Hashimoto, et al. Inhibition of NF{kappa}B Increases the Efficacy of Cisplatin in in Vitro and in Vivo Ovarian Cancer Models J. Biol. Chem., May 28, 2004; 279(22): 23477 - 23485. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Matei, D. D. Chang, and M.-H. Jeng Imatinib Mesylate (Gleevec) Inhibits Ovarian Cancer Cell Growth through a Mechanism Dependent on Platelet-Derived Growth Factor Receptor {alpha} and Akt Inactivation Clin. Cancer Res., January 15, 2004; 10(2): 681 - 690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Slavik, D.-G. Lim, S. J. Burakoff, and D. A. Hafler Rapamycin-resistant Proliferation of CD8+ T Cells Correlates with p27kip1 Down-regulation and bcl-xL Induction, and Is Prevented by an Inhibitor of Phosphoinositide 3-Kinase Activity J. Biol. Chem., January 9, 2004; 279(2): 910 - 919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Yu, M. Rahmani, D. Conrad, M. Subler, P. Dent, and S. Grant The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571 Blood, November 15, 2003; 102(10): 3765 - 3774. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. T. Lee and E. P. Kay Regulatory Role of cAMP on Expression of Cdk4 and p27Kip1 by Inhibiting Phosphatidylinositol 3-kinase in Corneal Endothelial Cells Invest. Ophthalmol. Vis. Sci., September 1, 2003; 44(9): 3816 - 3825. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Laurent, D. L. Mitchell, Z. Estrov, M. Lowery, S. L. Tucker, M. Talpaz, and R. Kurzrock Impact of p210Bcr-Abl on Ultraviolet C Wavelength-induced DNA Damage and Repair Clin. Cancer Res., September 1, 2003; 9(10): 3722 - 3730. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Nimmanapalli, L. Fuino, P. Bali, M. Gasparetto, M. Glozak, J. Tao, L. Moscinski, C. Smith, J. Wu, R. Jove, et al. Histone Deacetylase Inhibitor LAQ824 Both Lowers Expression and Promotes Proteasomal Degradation of Bcr-Abl and Induces Apoptosis of Imatinib Mesylate-sensitive or -refractory Chronic Myelogenous Leukemia-Blast Crisis Cells Cancer Res., August 15, 2003; 63(16): 5126 - 5135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rylski, J. J. Welch, Y.-Y. Chen, D. L. Letting, J. A. Diehl, L. A. Chodosh, G. A. Blobel, and M. J. Weiss GATA-1-Mediated Proliferation Arrest during Erythroid Maturation Mol. Cell. Biol., July 15, 2003; 23(14): 5031 - 5042. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Nimmanapalli, L. Fuino, C. Stobaugh, V. Richon, and K. Bhalla Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells Blood, April 15, 2003; 101(8): 3236 - 3239. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. T. Lee and E. P. Kay Regulatory Role of PI 3-Kinase on Expression of Cdk4 and p27, Nuclear Localization of Cdk4, and Phosphorylation of p27 in Corneal Endothelial Cells Invest. Ophthalmol. Vis. Sci., April 1, 2003; 44(4): 1521 - 1528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Komatsu, T. Watanabe, M. Uchida, M. Mori, K. Kirito, S. Kikuchi, Q. Liu, T. Tauchi, K. Miyazawa, H. Endo, et al. A Member of Forkhead Transcription Factor FKHRL1 Is a Downstream Effector of STI571-induced Cell Cycle Arrest in BCR-ABL-expressing Cells J. Biol. Chem., February 14, 2003; 278(8): 6411 - 6419. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Salesse and C. M. Verfaillie BCR/ABL-mediated Increased Expression of Multiple Known and Novel Genes That May Contribute to the Pathogenesis of Chronic Myelogenous Leukemia Mol. Cancer Ther., February 1, 2003; 2(2): 173 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. C. Roberts, P. S. Shapiro, T. S. Nahreini, G. Pages, J. Pouyssegur, and N. G. Ahn Distinct Cell Cycle Timing Requirements for Extracellular Signal-Regulated Kinase and Phosphoinositide 3-Kinase Signaling Pathways in Somatic Cell Mitosis Mol. Cell. Biol., October 15, 2002; 22(20): 7226 - 7241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. C. Dan, M. Sun, L. Yang, R. I. Feldman, X.-M. Sui, C. C. Ou, M. Nellist, R. S. Yeung, D. J. J. Halley, S. V. Nicosia, et al. Phosphatidylinositol 3-Kinase/Akt Pathway Regulates Tuberous Sclerosis Tumor Suppressor Complex by Phosphorylation of Tuberin J. Biol. Chem., September 13, 2002; 277(38): 35364 - 35370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-q. Yuan, R. I. Feldman, M. Sun, N. E. Olashaw, D. Coppola, G. E. Sussman, S. A. Shelley, S. V. Nicosia, and J. Q. Cheng Inhibition of JNK by Cellular Stress- and Tumor Necrosis Factor alpha -induced AKT2 through Activation of the NFkappa B Pathway in Human Epithelial Cells J. Biol. Chem., August 9, 2002; 277(33): 29973 - 29982. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Oki, A. Limnander, N. N. Danial, and P. B. Rothman Functional involvement of Akt signaling downstream of Jak1 in v-Abl-induced activation of hematopoietic cells Blood, July 18, 2002; 100(3): 966 - 973. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Slupianek, G. Hoser, I. Majsterek, A. Bronisz, M. Malecki, J. Blasiak, R. Fishel, and T. Skorski Fusion Tyrosine Kinases Induce Drug Resistance by Stimulation of Homology-Dependent Recombination Repair, Prolongation of G2/M Phase, and Protection from Apoptosis Mol. Cell. Biol., June 15, 2002; 22(12): 4189 - 4201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nieborowska-Skorska, G. Hoser, P. Kossev, M. A. Wasik, and T. Skorski Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis Blood, May 29, 2002; 99(12): 4531 - 4539. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Olashaw and W. J. Pledger Paradigms of Growth Control: Relation to Cdk Activation Sci. Signal., May 28, 2002; 2002(134): re7 - re7. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Holtz, M. L. Slovak, F. Zhang, C. L. Sawyers, S. J. Forman, and R. Bhatia Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation Blood, May 15, 2002; 99(10): 3792 - 3800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A. Barry and J. M. Gibbins Protein Kinase B Is Regulated in Platelets by the Collagen Receptor Glycoprotein VI J. Biol. Chem., April 5, 2002; 277(15): 12874 - 12878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Appleman, A. A. F. L. van Puijenbroek, K. M. Shu, L. M. Nadler, and V. A. Boussiotis CD28 Costimulation Mediates Down-Regulation of p27kip1 and Cell Cycle Progression by Activation of the PI3K/PKB Signaling Pathway in Primary Human T Cells J. Immunol., March 15, 2002; 168(6): 2729 - 2736. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Lawlor and D. R. Alessi PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J. Cell Sci., March 10, 2002; 114(16): 2903 - 2910. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Dierov, Q. Xu, R. Dierova, and M. Carroll TEL/platelet-derived growth factor receptor beta activates phosphatidylinositol 3 (PI3) kinase and requires PI3 kinase to regulate the cell cycle Blood, March 1, 2002; 99(5): 1758 - 1765. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Graham, H. G. Jorgensen, E. Allan, C. Pearson, M. J. Alcorn, L. Richmond, and T. L. Holyoake Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro Blood, January 1, 2002; 99(1): 319 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Richards New Signaling Pathways for Hormones and Cyclic Adenosine 3',5'-Monophosphate Action in Endocrine Cells Mol. Endocrinol., February 1, 2001; 15(2): 209 - 218. [Abstract] [Full Text]
|
|
|
|
|
|
Y. Parada, L. Banerji, J. Glassford, N. C. Lea, M. Collado, C. Rivas, J. L. Lewis, M. Y. Gordon, N. S. B. Thomas, and E. W.-F. Lam BCR-ABL and Interleukin 3 Promote Haematopoietic Cell Proliferation and Survival through Modulation of Cyclin D2 and p27Kip1 Expression J. Biol. Chem., June 22, 2001; 276(26): 23572 - 23580. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
