Article

Programmed Cell Death in Animal Development and Disease

Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Cell (Impact Factor: 33.12). 11/2011; 147(4):742-58. DOI: 10.1016/j.cell.2011.10.033
Source: PubMed

ABSTRACT Programmed cell death (PCD) plays a fundamental role in animal development and tissue homeostasis. Abnormal regulation of this process is associated with a wide variety of human diseases, including immunological and developmental disorders, neurodegeneration, and cancer. Here, we provide a brief historical overview of the field and reflect on the regulation, roles, and modes of PCD during animal development. We also discuss the function and regulation of apoptotic proteins, including caspases, the key executioners of apoptosis, and review the nonlethal functions of these proteins in diverse developmental processes, such as cell differentiation and tissue remodeling. Finally, we explore a growing body of work about the connections between apoptosis, stem cells, and cancer, focusing on how apoptotic cells release a variety of signals to communicate with their cellular environment, including factors that promote cell division, tissue regeneration, and wound healing.

0 Followers
 · 
240 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Earlier we showed formulation-specific beneficial effects of dietary supplement of Ayurvedic Amalaki Rasayana (AR, a herbal formulation) and Rasa-Sindoor (RS, a mercury-based organo-metallic formulation) on various biological parameters in Drosophila, parallel to traditional Ayurvedic literature. These formulations also suppressed cell death and pathology in fly models of neurodegeneration. To understand basis of inhibition of apoptosis, we examined effects of AR and RS on induced and developmental apoptosis in Drosophila. Dietary AR or RS significantly reduced apoptosis induced by GMR-GAL4-, sev-GAL4-or hs-GAL4-directed expression of Rpr, Hid or Grim (RHG) pro-apoptotic proteins or by GMR-GAL4-directed DIAP1-RNAi, resulting in significant restoration of organism's viability and eye morphology. AR or RS supplement enhanced levels of inhibitor of apoptosis proteins, DIAP1 and DIAP2, and of Bancal/Hrb57A, while the levels of RHG proteins and of initiator Dronc and effecter Drice caspases were reduced in non-apoptotic wild type as well as in RHG over-expressing tissues. Levels of Dronc or Drice remained unaffected in cells developmentally destined to die so that developmental apoptosis occurred normally. Elevated levels of DIAPs and reduced levels of RHG proteins and caspases reflect a more robust physiological state of AR or RS fed organisms allowing them to tolerate greater insults without triggering the cell-death response. Such homeo-static effects of these Rasayanas seem to contribute to 'healthy ageing', one of their effects suggested in traditional Ayurvedic practices. [Dwivedi V, Tiwary S and Lakhotia SC 2015 Suppression of induced but not developmental apoptosis in Drosophila by Ayurvedic Amalaki Rasayana and Rasa-Sindoor.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone; PLB), a naturally occurring naphthoquinone isolated from the roots of Plumbaginaceae plants, has been reported to possess anticancer activities in both in vitro and in vivo studies, but the effect of PLB on tongue squamous cell carcinoma (TSCC) is not fully understood. This study aimed to investigate the effects of PLB on cell cycle distribution, apoptosis, and autophagy, and the underlying mechanisms in the human TSCC cell line SCC25. The results have revealed that PLB exerted potent inducing effects on cell cycle arrest, apoptosis, and autophagy in SCC25 cells. PLB arrested SCC25 cells at the G2/M phase in a concentration- and time-dependent manner with a decrease in the expression level of cell division cycle protein 2 homolog (Cdc2) and cyclin B1 and increase in the expression level of p21 Waf1/Cip1, p27 Kip1, and p53 in SCC25 cells. PLB markedly induced apoptosis and autophagy in SCC25 cells. PLB decreased the expression of the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl) while increasing the expression level of the pro-apoptotic protein Bcl-2-associated X protein (Bax) in SCC25 cells. Furthermore, PLB inhibited phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β), and p38 mitogen-activated protein kinase (p38 MAPK) pathways as indicated by the alteration in the ratio of phosphorylation level over total protein expression level, contributing to the autophagy inducing effect. In addition, we found that wortmannin (a PI3K inhibitor) and SB202190 (a selective inhibitor of p38 MAPK) strikingly enhanced PLB-induced autophagy in SCC25 cells, suggesting the involvement of PI3K- and p38 MAPK-mediated signaling pathways. Moreover, PLB induced intracellular reactive oxygen species (ROS) generation and this effect was attenuated by l-glutathione (GSH) and n-acetyl-l-cysteine (NAC). Taken together, these results indicate that PLB promotes cellular apoptosis and autophagy in TSCC cells involving p38 MAPK- and PI3K/Akt/mTOR-mediated pathways with contribution from the GSK3β and ROS-mediated pathways.
    Drug Design, Development and Therapy 01/2015; 9:1601-26. DOI:10.2147/DDDT.S76057 · 3.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sclareol, a promising anticancer labdane diterpene, was isolated from Salvia sclarea. Keeping the basic stereochemistry rich framework of the molecule intact, the synthesis of novel sclareol analogues was designed using Palladium (II) catalyzed oxidative Heck coupling reaction for structure activity relationship (SAR). Both sclareol and its derivatives showed an interesting cytotoxicity profile with SS-12 as the most potent analogue having IC50 of 0.082 µM against PC-3 cells. It was found that SS-12 is commonly interacting with Bcl-2 and Beclin 1 BH3 domain proteins and enhances autophagic flux by modulating autophagy related proteins. Moreover, inhibition of autophagy by autophagy inhibitors protected SS-12-induced apoptosis. Finally, SS-12 effectively suppressed tumor growth in vivo in Ehrlich’s ascitic and solid Sarcoma-180 mouse models.
    Journal of Medicinal Chemistry 03/2015; · 5.48 Impact Factor

Full-text (2 Sources)

Download
38 Downloads
Available from
Jun 29, 2014