Evidence That Ser87 of BimEL Is Phosphorylated by Akt and Regulates BimEL Apoptotic Function

Qi, Xiaojun; Wildey, Gary; Howe, Philip H.

doi:10.1074/jbc.m505546200

Cited by 213 publications

(210 citation statements)

References 54 publications

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“…both extracellular signal-regulated kinase (ERK) and phosphoinositide-3-kinase (PI3K)/Akt-mediated phosphorylation of Bim, thus avoiding Bim proteasomal degradation and determining its accumulation [18,19]. In addition, loss of ECM contact, leading to disruption of Bim sequestration by dynein cytoskeleton complexes, strongly increases Bim cytoplasmic accumulation and increases Bad availability [17].…”

Section: Intrinsic Pathwaymentioning

confidence: 99%

Anoikis: an emerging hallmark in health and diseases

Taddei

Giannoni

Fiaschi

et al. 2011

The Journal of Pathology

466

404

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Anoikis is a programmed cell death occurring upon cell detachment from the correct extracellular matrix, thus disrupting integrin ligation. It is a critical mechanism in preventing dysplastic cell growth or attachment to an inappropriate matrix. Anoikis prevents detached epithelial cells from colonizing elsewhere and is thus essential for tissue homeostasis and development. As anchorage-independent growth and epithelial-mesenchymal transition, two features associated with anoikis resistance, are crucial steps during tumour progression and metastatic spreading of cancer cells, anoikis deregulation has now evoked particular attention from the scientific community. The aim of this review is to analyse the molecular mechanisms governing both anoikis and anoikis resistance, focusing on their regulation in physiological processes, as well as in several diseases, including metastatic cancers, cardiovascular diseases and diabetes.

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Section: Intrinsic Pathwaymentioning

confidence: 99%

Anoikis: an emerging hallmark in health and diseases

Taddei

Giannoni

Fiaschi

et al. 2011

The Journal of Pathology

466

404

View full text Add to dashboard Cite

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“…Akt has also been shown to phosphorylate the pro-apoptotic protein Bim 223,224 , allowing the release of pro-survival proteins and targeting Bim for degradation. Akt can also block the transcription of Bim by targeting the forkhead transcription factor FOXO3A for phosphorylation leading to its association with the 14-3-3 proteins and targeting it for degradation 225,226 .…”

Section: The Akt Pathwaymentioning

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

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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.

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“…Bim's activity is regulated by phosphorylation at different residues by Akt, ERK and c-Jun N-terminal kinase. [107][108][109] When Bim is phosphorylated by Akt and ERK, it is targeted for proteasomal degradation and also inhibits Bim's interaction with Bax, a death executioner protein. In contrast, when Bim is phosphorylated by c-Jun N-terminal kinase, it has enhanced pro-apoptotic activity.…”

Section: Targeting Translation Governed By Pi3k Pathway Am Martelli Ementioning

confidence: 99%