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Sustained Akt/PKB activation and transient attenuation of c-jun N-terminal kinase in the inhibition of apoptosis by IGF-1 in vascular smooth muscle cells.
Apoptosis. 2005 May; 10(3):525-35.A

Abstract

Characteristics of hVSMC apoptosis and its inhibition by insulin-like growth factor-1 (IGF-1) remain unclear. Also unclear is whether a balance in hVSMCs exists whereby c-Jun N-terminal stress kinases (JNK) promote apoptosis while extracellular signal-regulated (ERK1/2) MAP kinases inhibit cell death. In this study, we examined the involvement of Akt/PKB and its upstream kinase, PDK1 and whether JNK activation correlated with human and rat VSMC apoptosis induced by staurosporine and by c-myc, respectively. We observed a strong, sustained JNK activation (and c-Jun phosphorylation), which correlated with VSMC apoptosis. IGF-1 (13.3 nM), during apoptosis inhibition, transiently inhibited JNK activity at 1 h in a phosphatidylinositol 3-kinase (PI3-K)- and MEK-ERK-dependent manner, as wortmannin (100 nM) or PD98059 (30 muM) partially attenuated the IGF-1 effect. PKC down-regulation had no effect on JNK inhibition by IGF-1. While IGF-1 alone produced a strong phosphorylation of Akt/PKB in hVSMCs up to 6 h, it was notably stronger and more sustained during ratmyc and hVSMCs apoptosis inhibition. Further, whereas transient expression of phosphorylated Akt protected VSMCs from apoptosis by nearly 50%, expression of dominant interfering alleles of Akt or PDK1 strongly inhibited IGF-1-mediated VSMC survival. These results demonstrate for the first time that transient inhibition of a pro-apoptotic stimulus in VSMCs may be sufficient to inhibit a programmed cell death and that sustained anti-apoptotic signals (Akt) elicited by IGF-1 are augmented during a death stimulus. Furthermore, PI3-K and ERK-MAPK pathways may cooperate to protect VSMCs from cell death.

Authors+Show Affiliations

Departments of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15909115

Citation

Allen, R T., et al. "Sustained Akt/PKB Activation and Transient Attenuation of C-jun N-terminal Kinase in the Inhibition of Apoptosis By IGF-1 in Vascular Smooth Muscle Cells." Apoptosis : an International Journal On Programmed Cell Death, vol. 10, no. 3, 2005, pp. 525-35.
Allen RT, Krueger KD, Dhume A, et al. Sustained Akt/PKB activation and transient attenuation of c-jun N-terminal kinase in the inhibition of apoptosis by IGF-1 in vascular smooth muscle cells. Apoptosis. 2005;10(3):525-35.
Allen, R. T., Krueger, K. D., Dhume, A., & Agrawal, D. K. (2005). Sustained Akt/PKB activation and transient attenuation of c-jun N-terminal kinase in the inhibition of apoptosis by IGF-1 in vascular smooth muscle cells. Apoptosis : an International Journal On Programmed Cell Death, 10(3), 525-35.
Allen RT, et al. Sustained Akt/PKB Activation and Transient Attenuation of C-jun N-terminal Kinase in the Inhibition of Apoptosis By IGF-1 in Vascular Smooth Muscle Cells. Apoptosis. 2005;10(3):525-35. PubMed PMID: 15909115.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sustained Akt/PKB activation and transient attenuation of c-jun N-terminal kinase in the inhibition of apoptosis by IGF-1 in vascular smooth muscle cells. AU - Allen,R T, AU - Krueger,K D, AU - Dhume,A, AU - Agrawal,D K, PY - 2005/5/24/pubmed PY - 2005/9/28/medline PY - 2005/5/24/entrez SP - 525 EP - 35 JF - Apoptosis : an international journal on programmed cell death JO - Apoptosis VL - 10 IS - 3 N2 - Characteristics of hVSMC apoptosis and its inhibition by insulin-like growth factor-1 (IGF-1) remain unclear. Also unclear is whether a balance in hVSMCs exists whereby c-Jun N-terminal stress kinases (JNK) promote apoptosis while extracellular signal-regulated (ERK1/2) MAP kinases inhibit cell death. In this study, we examined the involvement of Akt/PKB and its upstream kinase, PDK1 and whether JNK activation correlated with human and rat VSMC apoptosis induced by staurosporine and by c-myc, respectively. We observed a strong, sustained JNK activation (and c-Jun phosphorylation), which correlated with VSMC apoptosis. IGF-1 (13.3 nM), during apoptosis inhibition, transiently inhibited JNK activity at 1 h in a phosphatidylinositol 3-kinase (PI3-K)- and MEK-ERK-dependent manner, as wortmannin (100 nM) or PD98059 (30 muM) partially attenuated the IGF-1 effect. PKC down-regulation had no effect on JNK inhibition by IGF-1. While IGF-1 alone produced a strong phosphorylation of Akt/PKB in hVSMCs up to 6 h, it was notably stronger and more sustained during ratmyc and hVSMCs apoptosis inhibition. Further, whereas transient expression of phosphorylated Akt protected VSMCs from apoptosis by nearly 50%, expression of dominant interfering alleles of Akt or PDK1 strongly inhibited IGF-1-mediated VSMC survival. These results demonstrate for the first time that transient inhibition of a pro-apoptotic stimulus in VSMCs may be sufficient to inhibit a programmed cell death and that sustained anti-apoptotic signals (Akt) elicited by IGF-1 are augmented during a death stimulus. Furthermore, PI3-K and ERK-MAPK pathways may cooperate to protect VSMCs from cell death. SN - 1360-8185 UR - https://www.unboundmedicine.com/medline/citation/15909115/Sustained_Akt/PKB_activation_and_transient_attenuation_of_c_jun_N_terminal_kinase_in_the_inhibition_of_apoptosis_by_IGF_1_in_vascular_smooth_muscle_cells_ L2 - https://doi.org/10.1007/s10495-005-1882-3 DB - PRIME DP - Unbound Medicine ER -