Microtubule-targeting drugs induce Bcl-2 phosphorylation and association with Pin1.
Bcl-2 is a critical suppressor of apoptosis that is overproduced in many types of cancer. Phosphorylation of the Bcl-2 protein is induced on serine residues in tumor cells arrested by microtubule-targeting drugs (paclitaxel, vincristine, nocodazole) and has been associated with inactivation of antiapoptotic function through an unknown mechanism. Comparison of ... a variety of pharmacological inhibitors of serine/threonine-specific protein kinases demonstrated that the cyclin-dependent kinase inhibitor, flavopiridol, selectively blocks Bcl-2 phosphorylation induced by antimicrotubule drugs. Bcl-2 could also be coimmunoprecipitated with the kinase Cdc2 in M-phase-arrested cells, suggesting that a Cdc2 may be responsible for phosphorylation of Bcl-2 in cells treated with microtubule-targeting drugs. Examination of several serine-->alanine substitution mutants of Bcl-2 suggested that serine 70 and serine 87 represent major sites of Bcl-2 phosphorylation induced in response to microtubule-targeting drugs. Both these serines are within sequence contexts suitable for proline-directed kinases such as Cdc2. Phosphorylated Bcl-2 protein was discovered to associate in M-phase-arrested cells with Pin1, a mitotic peptidyl prolyl isomerase (PPIase) known to interact with substrates of Cdc2 during mitosis. In contrast, phosphorylation of Bcl-2 induced by microtubule-targeting drugs did not alter its ability to associate with Bcl-2 (homodimerization), Bax, BAG1, or other Bcl-2-binding proteins. Since the region in Bcl-2 containing serine 70 and serine 87 represents a proline-rich loop that has been associated with autorepression of its antiapoptotic activity, the discovery of Pin1 interactions with phosphorylated Bcl-2 raises the possibility that Pin1 alters the conformation of Bcl-2 and thereby modulates its function in cells arrested with antimicrotubule drugs.
Mesh Terms:
Antineoplastic Agents, Apoptosis, Cyclin-Dependent Kinases, Enzyme Activation, Enzyme Inhibitors, Glutathione Transferase, Humans, Microtubules, Mitosis, Peptidylprolyl Isomerase, Phosphorylation, Precipitin Tests, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-bcl-2, Structure-Activity Relationship, Tumor Cells, Cultured
Antineoplastic Agents, Apoptosis, Cyclin-Dependent Kinases, Enzyme Activation, Enzyme Inhibitors, Glutathione Transferase, Humans, Microtubules, Mitosis, Peptidylprolyl Isomerase, Phosphorylation, Precipitin Tests, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-bcl-2, Structure-Activity Relationship, Tumor Cells, Cultured
Neoplasia
Date: Apr. 28, 2001
PubMed ID: 11326318
View in: Pubmed Google Scholar
Download Curated Data For This Publication
4853
Switch View:
- Interactions 2