Role for c-Abl tyrosine kinase in growth arrest response to DNA damage

Nature ◽  
1996 ◽  
Vol 382 (6588) ◽  
pp. 272-274 ◽  
Author(s):  
Zhi-Min Yuan ◽  
Yinyin Huang ◽  
Young Whang ◽  
Charles Sawyers ◽  
Ralph Weichselbaum ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tyrosine Kinase ◽  
Growth Arrest ◽  
Abl Tyrosine Kinase

scholarly journals c-Abl Tyrosine Kinase Regulates Caspase-9 Autocleavage in the Apoptotic Response to DNA Damage

2005 ◽  
Vol 280 (12) ◽  
pp. 11147-11151 ◽  
Author(s):  
Deepak Raina ◽  
Pramod Pandey ◽  
Rehan Ahmad ◽  
Ajit Bharti ◽  
Jian Ren ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tyrosine Kinase ◽  
Caspase 9 ◽  
Apoptotic Response ◽  
Abl Tyrosine Kinase

Proliferating cell nuclear antigen destabilizes c-Abl tyrosine kinase and regulates cell apoptosis in response to DNA damage

APOPTOSIS ◽  
2009 ◽  
Vol 14 (3) ◽  
pp. 268-275 ◽  
Author(s):  
Xiang He ◽  
Congwen Wei ◽  
Ting Song ◽  
Jing Yuan ◽  
Yanhong Zhang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tyrosine Kinase ◽  
Cell Apoptosis ◽  
Proliferating Cell Nuclear Antigen ◽  
Nuclear Antigen ◽  
Abl Tyrosine Kinase ◽  
Proliferating Cell

scholarly journals Growth Suppression by an E2F-Binding-Defective Retinoblastoma Protein (RB): Contribution from the RB C Pocket

1998 ◽  
Vol 18 (7) ◽  
pp. 4032-4042 ◽  
Author(s):  
Laura L. Whitaker ◽  
Heyun Su ◽  
Rajasekaran Baskaran ◽  
Erik S. Knudsen ◽  
Jean Y. J. Wang
Keyword(s):  
Cell Growth ◽  
Tyrosine Kinase ◽  
Protein Binding ◽  
Growth Arrest ◽  
Retinoblastoma Protein ◽  
Growth Suppression ◽  
Peptide Motif ◽  
Abl Tyrosine Kinase ◽  
Transcription Regulators

ABSTRACT Growth suppression by the retinoblastoma protein (RB) is dependent on its ability to form complexes with transcription regulators. At least three distinct protein-binding activities have been identified in RB: the large A/B pocket binds E2F, the A/B pocket binds the LXCXE peptide motif, and the C pocket binds the nuclear c-Abl tyrosine kinase. Substitution of Trp for Arg 661 in the B region of RB (mutant 661) inactivates both E2F and LXCXE binding. The tumor suppression function of mutant 661 is not abolished, because this allele predisposes its carriers to retinoblastoma development with a low penetrance. In cell-based assays, 661 is shown to inhibit G1/S progression. This low-penetrance mutant also induces terminal growth arrest with reduced but detectable activity. We have constructed mutations that disrupt C pocket activity. When overproduced, the RB C-terminal fragment did not induce terminal growth arrest but could inhibit G1/S progression, and this activity was abolished by the C-pocket mutations. In full-length RB, the C-pocket mutations reduced but did not abolish RB function. Interestingly, combination of the C-pocket and 661 mutations completely abolished RB’s ability to cause an increase in the percentage of cells in G1 and to induce terminal growth arrest. These results suggest that the A/B or C region can induce a prolongation of G1 through mechanisms that are independent of each other. In contrast, long-term growth arrest requires combined activities from both regions of RB. In addition, E2F and LXCXE binding are not the only mechanisms through which RB inhibits cell growth. The C pocket also contributes to RB-mediated growth suppression.

c-ABL tyrosine kinase modulates p53-dependent p21 induction and ensuing cell fate decision in response to DNA damage

2014 ◽  
Vol 26 (2) ◽  
pp. 444-452 ◽  
Author(s):  
S.M. Nashir Udden ◽  
Yuiko Morita-Fujimura ◽  
Masanobu Satake ◽  
Shuntaro Ikawa
Keyword(s):  
Dna Damage ◽  
Tyrosine Kinase ◽  
Cell Fate ◽  
Cell Fate Decision ◽  
Abl Tyrosine Kinase ◽  
Fate Decision

Rewiring of the Protein Kinase C Beta 2 (PKC βII) and Bcr/Abl Signal Transduction Pathways

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1673-1673
Author(s):  
David Arthur Hoekstra ◽  
Louise M Carlson ◽  
Kelvin P Lee
Keyword(s):  
Signal Transduction ◽  
Plasma Membrane ◽  
Tyrosine Kinase ◽  
Growth Arrest ◽  
K562 Cells ◽  
Signal Transduction Pathways ◽  
Abl Kinase ◽  
Abl Tyrosine Kinase ◽  
Induction Of Apoptosis ◽  
Constitutively Active

Abstract Abstract 1673 Chronic myeloid leukemia (CML) accounts for 20% of adult leukemias, and is characterized by the presence of the bcr-abl fusion gene. This gene leads to the production of a constitutively active Abl tyrosine kinase, which promiscuously phosphorylates/activates a variety of intracellular signal transduction pathways. The presence of constitutively active Abl is essential for CML blast survival even in advanced disease, and underlies the success that the Bcr/Abl kinase inhibitor imatinib has had. However, resistance to imatinib occurs in a significant number of accelerated phase or blast crisis patients and is a significant clinical obstacle. Instead of trying to inhibit Bcr/Abl signaling, we propose a previously unexplored approach to ‘rewire’ kinase signaling pathways to activate a “suicide” prodrug that would not normally be activated by Bcr/Abl. We have previously shown that direct activation of PKCβII by Phorbol 12-myristate 13-acetate (PMA) drives dendritic cell differentiation in both normal and leukemic progenitors, as well as induces apoptosis and growth arrest. PKCβII is a member of the PKC family of serine/threonine kinases and is kept in an inactive state in the cytosol by interactions between its pseudosubstrate and kinase domains; upon activation, the pseudosubstrate domain releases the kinase domain, and PKCβII translocates to the plasma membrane. Substitution of an alanine at position 25 in the pseudosubstrate domain for a phosphomimetic glutamic acid leads to the constitutive activation of PKCβII. Similarly, we hypothesized that substituting the alanine at position 25 for a phosphorylatable tyrosine (A25Y) along with the corresponding Bcr/Abl kinase target motif (Ala-X-X-Ile-Tyr-X-X-Phe/Pro) into the pseudosubstrate domain of PKCβII, would allow the Bcr/Abl tyrosine kinase to activate the PKCβII signaling pathway. Bcr/Abl mediated activation of PKCβII would then lead to the induction of apoptosis, growth inhibition, and differentiation. Using confocal microscopy, we show that following transfection WT-PKCβII is cytoplasmically located in media alone and addition of PMA leads to translocation to the plasma membrane, indicating activation in both Bcr/Abl+ K562 cells, and Bcr/Abl− KG1a cells. However when A25Y-PKCβII constructs are transfected in, A25Y-PKCβII is found at the plasma membrane in K562, but not in KG1a cells in media alone. These observations were then quantified using ImageStream technology, which allows for simultaneous acquisition of both flow cytometric data, and high resolution fluorescent images. Using this technology, we show that A25Y-PKCβII is activated in media alone in K562 cells, and only upon addition of PMA in KG1a cells. Additionally, when Bcr/Abl was stably transfected in KG1a cells, A25Y-PKCβII was able to translocate to the plasma membrane in media alone, indicating activation by Bcr/Abl. Upon activation and translocation to the plasma membrane, PKCβII is rapidly degraded; accordingly, we show that expression of WT PKCβII decreases only by 20% over 72 hours post transfection, whereas expression of A25Y-PKCβII results in an average decrease of 90% over the same 72 hour time course. To test whether activation of A25Y-PKCβII leads to apoptosis and growth arrest, Bcr/Abl+ K562, and Bcr/Abl− KG1a cells were transfected with either WT and A25Y-PKCβII and measured for apoptosis with AnnexinV using Flow Cytometry. We found that A25Y-PKCβII induced a maximum of a 4-fold increase of apoptosis when compared to WT PKCβII in K562 cells; however there was no increase observed in KG1a cells. This work demonstrates that rewiring PKCβII to be inducible by Bcr/Abl is feasible, and that activation of PKCβII by Bcr/Abl induces characteristic translocation to the plasma membrane, and induction of apoptosis. Future work will address whether induction of DC differentiation is maintained in Bcr/Abl activated PKCβII cells, as well as the molecular kinetics of this activation. Disclosures: No relevant conflicts of interest to declare.

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