Depletion of p185 erbB2 , Raf-1 and mutant p53 proteins by geldanamycin derivatives correlates with antiproliferative activity

An, Won Gun; Schnur, Rodney C.; Neckers, Len; Blagosklonny, Mikhail V.

doi:10.1007/s002800050626

Cited by 105 publications

(65 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This observation is consistent with the notion that Raf-1 and Bcl-2 phosphorylation is tightly coupled although it does not prove that Raf-1 mediates Bcl-2 phosphorylation. Thus, depletion of Raf-1 by GA causes growth arrest, 39 and this may preclude mitotic arrest by paclitaxel. Although, the role of Raf-1 in Bcl-2 phosphorylation remains circumstantial, the two events are tightly associated, because both of them occurs during mitotic arrest.…”

Section: Phosphorylation Of Raf-1/bcl-2 By Paclitaxel In Lckdeficientmentioning

confidence: 99%

Mitogen-activated protein kinase pathway is dispensable for microtubule-active drug-induced Raf-1/Bcl-2 phosphorylation and apoptosis in leukemia cells

Chuman

Bergan

et al. 1999

Leukemia

View full text Add to dashboard Cite

Raf-1 activation and Bcl-2 hyperphosphorylation following treatment with paclitaxel (Taxol) or other microtubule-active drugs is associated with mitotic arrest. Here we show that microtubule-active drugs do not activate the mitogen-activated protein kinase (MAPK) pathway in leukemia cells. PD98059, a MEK inhibitor, and SB202190, a p38 MAP kinase inhibitor, do not abrogate Bcl-2 phosphorylation nor apoptosis. Simultaneously with PARP cleavage, paclitaxel induces cleavage of Bcl-2 protein yielding a potentially pro-apoptotic 22 kDa product. In comparison, the stimulation of Raf-1 by phorbol ester (TPA) activates the MAPK pathway, causes MAPK-dependent p21 WAF1/CIP1 induction, Rb dephosphorylation and growth arrest without Bcl-2 phosphorylation or apoptosis. Like TPA, cAMP induces p21 WAF1/CIP1 but does not cause Bcl-2 phosphorylation. MEKK1 and Ras, upstream activators of JNK and ERK MAPK, also fail to induce Bcl-2 hyperphosphorylation. Although Lck tyrosine kinase has been recently implicated in Raf-1 activation during mitotic arrest, microtubule-active drugs induce Raf-1/Bcl-2 hyperphosphorylation and apoptosis in a Lck-deficient Jurkat cells. Therefore, microtubule-active drugs induce apoptosis which is associated with Raf-1 and Bcl-2 phosphorylation and Bcl-2 cleavage but is independent of the MAPK pathway. In contrast, TPA-activated MAPK pathway causes p21 WAF1/CIP1 -dependent growth arrest without apoptosis.

show abstract

Section: Phosphorylation Of Raf-1/bcl-2 By Paclitaxel In Lckdeficientmentioning

confidence: 99%

Mitogen-activated protein kinase pathway is dispensable for microtubule-active drug-induced Raf-1/Bcl-2 phosphorylation and apoptosis in leukemia cells

Chuman

Bergan

et al. 1999

Leukemia

View full text Add to dashboard Cite

show abstract

“…7,50,66 Yet, GA depleted other proteins as well. 67 Most importantly, depletion of Raf-1 and other kinases inhibited cell proliferation, thus precluding mitotic arrest caused by microtubule-active drugs. Hyperphosphorylation of both Raf-1 and Bcl-2 occurs in mitosis and therefore were closely associated.…”

Section: What Kinase Phosphorylates Bcl-2 In Mitotic Arrest?mentioning

confidence: 99%

Unwinding the loop of Bcl-2 phosphorylation

2001

Leukemia

126

132

View full text Add to dashboard Cite

Recent evidence indicates that anti-apoptotic functions of Bcl-2 can be regulated by its phosphorylation. According to the 'mitotic arrest-induced' model, multi-site phosphorylation of the Bcl-2 loop domain is followed by cell death. In contrast, in cytokine-dependent cell lines, cytokines mediate phosphorylation of Bcl-2 on S70, preventing apoptosis. As discussed in this review, these models are not mutually exclusive but reflect different cellular contexts. During mitotic arrest, signal transduction is unique and is fundamentally different from classical mitogenic signaling, since the nucleus membrane is dissolved, gene expression is reduced, and numerous kinases and regulatory proteins are hyperphosphorylated. Hyperphosphorylation of Bcl-2 mediated by paclitaxel and other microtubuleactive drugs is strictly dependent on targeting microtubules that in turn cause mitotic arrest. In addition to serine-70 (S70), microtubule-active agents promote phosphorylation of S87 and threonine-69 (T69), inactivating Bcl-2. A major obstacle for identification of the mitotic Bcl-2 kinase(s) is that inhibition of putative kinase(s) by any means (dominant-negative mutants, antisense oligonucleotides, pharmacological agents) may arrest cycle, preventing mitosis and Bcl-2 phosphorylation. The role of Bcl-2 phosphorylation in cell death is discussed. Leukemia (2001) 15, 869-874.

show abstract

“…Proteins were resolved with SDS-PAGE as previously described. 15,17 Immunoblotting was performed using rabbit polyclonal anti-human PARP (Upstate Biotechnology, Lake Placid, NY, USA), for Bcr using monoclonal anti-human Bcr antibodies N 2 (Oncogene Science, Calbiochem, San Diego, CA, USA).…”

Section: Immunoblot Analysismentioning

confidence: 99%

The Hsp90 inhibitor geldanamycin selectively sensitizes Bcr-Abl-expressing leukemia cells to cytotoxic chemotherapy

et al. 2001

View full text Add to dashboard Cite

Depletion of p185 erbB2 , Raf-1 and mutant p53 proteins by geldanamycin derivatives correlates with antiproliferative activity

Abstract: These findings suggest that GA and its derivatives are cytostatic/cytotoxic at concentrations that also downregulate Raf-1, p185erbB2 and mutant p53, and raise the possibility that depletion of these proteins and the antiproliferative activities of GA have a common mechanism.

Cited by 105 publications

References 15 publications

Mitogen-activated protein kinase pathway is dispensable for microtubule-active drug-induced Raf-1/Bcl-2 phosphorylation and apoptosis in leukemia cells

Mitogen-activated protein kinase pathway is dispensable for microtubule-active drug-induced Raf-1/Bcl-2 phosphorylation and apoptosis in leukemia cells

Unwinding the loop of Bcl-2 phosphorylation

The Hsp90 inhibitor geldanamycin selectively sensitizes Bcr-Abl-expressing leukemia cells to cytotoxic chemotherapy

Contact Info

Product

Resources

About