Apoptosis and survival - nAChR in apoptosis inhibition and cell cycle progression

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nAChR in apoptosis inhibition and cell cycle progression

Nicotinic acetylcholine receptors (nAChR) are pentameric proteins comprising either combinations of two different types of subunit (nAChR alpha and nAChR beta) or five copies of the same alpha subunit symmetrically arranged around a central ion pore [1].

nAChR alpha-7 form a signaling complex with Fyn and PI3K reg class IA (p85). PI3K reg class IA (p85) is a regulatory subunit of PI3K cat class IA and may activate the latter one upon nAChR alpha-7 stimulation by Nicotine. PI3K cat class IA is an enzyme that converts Phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2) to Phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3). PtdIns(3,4,5)P3 is a second messenger that directly binds via pleckstrin homology (PH) domen with V-akt murine thymoma viral oncogene homolog (AKT(PKB)) leading to activation of latter one by 3-phosphoinositide dependent protein kinase-1 (PDK(PDPK1)). PI3K/AKT pathway plays important role in cell proliferation and survival. AKT(PKB) activates FK506 binding protein 12-rapamycin associated protein 1 (mTOR), apparently through Tuberin/ GTP-binding protein Ras homolog enriched in brain (RHEB) pathway. mTOR phosphorylates and inactivates Eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1). mTOR also activates Ribosomal protein 6S kinase 70kDa, polypeptide 1 (p70S6 kinase1) by phosphorylation. AKT(PKB) inhibits apoptosis through Forkhead box O1 (FKHR) inactivation and phosphorylation, it also phosphorylates and inactivates glycogen synthase kinase 3 alpha (GSK3 alpha) and Glycogen synthase kinase 3 beta (GSK3 beta) [2], [3], [4], [5].

Nicotine stimulation causes the assembly of oligomeric complexes involving Beta-arrestin1, V-src sarcoma viral oncogene homolog (c-Src), and nAChRs, facilitating the activation of c-Src. This leads to the phosphorylation and activation of V-raf-leukemia viral oncogene 1 (Raf-1) which binds to Rb protein and therefore stimulates cell cycle progression [6].

References:

  1. Egleton RD, Brown KC, Dasgupta P
    Nicotinic acetylcholine receptors in cancer: multiple roles in proliferation and inhibition of apoptosis. Trends in pharmacological sciences 2008 Mar;29(3):151-8
  2. Kihara T, Shimohama S, Sawada H, Honda K, Nakamizo T, Shibasaki H, Kume T, Akaike A
    alpha 7 nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block A beta-amyloid-induced neurotoxicity. The Journal of biological chemistry 2001 Apr 27;276(17):13541-6
  3. West KA, Brognard J, Clark AS, Linnoila IR, Yang X, Swain SM, Harris C, Belinsky S, Dennis PA
    Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. The Journal of clinical investigation 2003 Jan;111(1):81-90
  4. Sun X, Ritzenthaler JD, Zhong X, Zheng Y, Roman J, Han S
    Nicotine stimulates PPARbeta/delta expression in human lung carcinoma cells through activation of PI3K/mTOR and suppression of AP-2alpha. Cancer research 2009 Aug 15;69(16):6445-53
  5. Akaike A, Takada-Takatori Y, Kume T, Izumi Y
    Mechanisms of neuroprotective effects of nicotine and acetylcholinesterase inhibitors: role of alpha4 and alpha7 receptors in neuroprotection. Journal of molecular neuroscience : MN 2010 Jan;40(1-2):211-6
  6. Dasgupta P, Rastogi S, Pillai S, Ordonez-Ercan D, Morris M, Haura E, Chellappan S
    Nicotine induces cell proliferation by beta-arrestin-mediated activation of Src and Rb-Raf-1 pathways. The Journal of clinical investigation 2006 Aug;116(8):2208-2217

  1. Egleton RD, Brown KC, Dasgupta P
    Nicotinic acetylcholine receptors in cancer: multiple roles in proliferation and inhibition of apoptosis. Trends in pharmacological sciences 2008 Mar;29(3):151-8
  2. Kihara T, Shimohama S, Sawada H, Honda K, Nakamizo T, Shibasaki H, Kume T, Akaike A
    alpha 7 nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block A beta-amyloid-induced neurotoxicity. The Journal of biological chemistry 2001 Apr 27;276(17):13541-6
  3. West KA, Brognard J, Clark AS, Linnoila IR, Yang X, Swain SM, Harris C, Belinsky S, Dennis PA
    Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. The Journal of clinical investigation 2003 Jan;111(1):81-90
  4. Sun X, Ritzenthaler JD, Zhong X, Zheng Y, Roman J, Han S
    Nicotine stimulates PPARbeta/delta expression in human lung carcinoma cells through activation of PI3K/mTOR and suppression of AP-2alpha. Cancer research 2009 Aug 15;69(16):6445-53
  5. Akaike A, Takada-Takatori Y, Kume T, Izumi Y
    Mechanisms of neuroprotective effects of nicotine and acetylcholinesterase inhibitors: role of alpha4 and alpha7 receptors in neuroprotection. Journal of molecular neuroscience : MN 2010 Jan;40(1-2):211-6
  6. Dasgupta P, Rastogi S, Pillai S, Ordonez-Ercan D, Morris M, Haura E, Chellappan S
    Nicotine induces cell proliferation by beta-arrestin-mediated activation of Src and Rb-Raf-1 pathways. The Journal of clinical investigation 2006 Aug;116(8):2208-2217

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