p90RSK Blocks Bad-mediated Cell Death via a Protein Kinase C-dependent Pathway

Tan, Yi; Ruan, Hong; Demeter, Matthew R.; Comb, Michael J.

doi:10.1074/jbc.274.49.34859

Cited by 221 publications

(200 citation statements)

References 59 publications

Supporting

Mentioning

183

Contrasting

Order By: Relevance

“…Bad is inactivated by phosphorylation through the MAPK pathway, with ERK phosphorylating p90Rsk, which in turn phosphorylates Bad at amino acid (aa) 75 (aa112 in mice) 292 . Akt can also phosphorylate Bad at aa999 (aa136 nin mice) 293 and PKA can phosphorylate it at aa118 (aa155 in mice) 294 .…”

Section: Regulation Of the Bh3-only Proteinsmentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

View full text Add to dashboard Cite

Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

show abstract

Section: Regulation Of the Bh3-only Proteinsmentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

View full text Add to dashboard Cite

show abstract

“…46 p90RSK signalling also blocks Bad-mediated death through a PKC-dependent pathway. 126 Indeed, PKC itself has also been reported to activate Raf. 47 Thus, several of the effects of Ras and Bcl-2 in leukaemia, such as disease aggression and chemoresistance, may be at least partially mediated by PKC, or rely on PKC activity as a co-operating lesion.…”

Section: Pkc and Multidrug Resistancementioning

confidence: 99%

Molecular signals in anti-apoptotic survival pathways

O'Gorman

Cotter

2001

Leukemia

View full text Add to dashboard Cite

Drug resistance, to date, has primarily been attributed to increased drug export or detoxification mechanisms. Despite correlations between drug export and drug resistance, it is increasingly apparent that such mechanisms cannot fully account for chemoresistance in neoplasia. It is now widely accepted that chemotherapeutic drugs kill tumour cells by inducing apoptosis, a genetically regulated cell death programme. Evidence is emerging that the exploitation of survival pathways, which may have contributed to disease development in the first instance, may also be important in the development of the chemoresistance. This review discusses the components of and associations between multiple signalling cascades and their possible contribution to the development of neoplasia and the chemoresistant phenotype. Leukemia (2001) 15, 21-34.

show abstract

“…p90 Rsk has been shown to phosphorylate BAD on serine residue 112. 106,107 Thus not only are the kinases upstream of Erk involved in the prevention of apoptosis but in addition the kinases downstream of Erk activation appear to play an important role in preventing apoptosis.…”

Section: The Ras/raf/mek/erk Signaling Kinase Cascadementioning

confidence: 99%

Kinases: positive and negative regulators of apoptosis

2000

View full text Add to dashboard Cite

Cells sense and respond to extracellular factors via receptors on the cell surface that trigger intracellular signaling pathways. The signals received by the receptors on hematopoietic cells often determine if the cell proliferates, survives or undergoes apoptosis. Apoptosis can be induced by almost any cytotoxic stimuli. These stimuli may be an absence of signals arising from cellular receptors, stimulation of specific ligand receptors on the cell surface, chemotherapeutic agents, and ionizing radiation or oxygen radicals, as well as a number of other factors. Cellular kinases and phosphatases participate in signaling cascades that influence this process. We review the ability of the calmodulin-dependent-kinases, I-B kinases, PI3-kinases, Jakkinases, PKC, PKA, and MAP kinase signaling pathways (Erk, Jnk, and p38), to influence the apoptotic process. In addition, we discuss the cross-talk that exists between signaling cascades that are pro-apoptotic and anti-apoptotic.

show abstract

p90RSK Blocks Bad-mediated Cell Death via a Protein Kinase C-dependent Pathway

Cited by 221 publications

References 59 publications

Role of the pro-survival molecule Bfl-1 in melanoma

Role of the pro-survival molecule Bfl-1 in melanoma

Molecular signals in anti-apoptotic survival pathways

Kinases: positive and negative regulators of apoptosis

Contact Info

Product

Resources

About