Dual role of proapoptotic BAD in insulin secretion and beta cell survival

Danial, Nika N.; Walensky, Loren D.; Zhang, Chenyu; Choi, Cheol Soo; Fisher, Jill K.; Molina, Anthony J.A.; Datta, Sandeep Robert; Pitter, Kenneth L.; Bird, Gregory H.; Wikström, Jakob D.; Deeney, Jude T.; Robertson, Kirsten; Morash, Joel; Kulkarni, Ameya; Neschen, Susanne; Kim, Sheene; Greenberg, Michael E.; Corkey, Barbara E.; Shirihai, Orian S.; Shulman, Gerald I.; Lowell, Bradford B.; Korsmeyer, Stanley J.

doi:10.1038/nm1717

Cited by 292 publications

(388 citation statements)

References 53 publications

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“…Several cell-penetrant stapled peptides have previously been described, although this property is normally assessed using flow cytometry and confocal fluorescence microscopy, requiring the need for fluorescently labeled peptides. [22][23][24][25]36,37 Nevertheless, the results presented here highlight just how critical the studied system is to the properties of interest and how complex it is to generalize and transpose observations in medicinal chemistry. 27 Starting from native VIP, a number of stapled analogues were designed and synthesized to evaluate the effect of their helical content on the interaction with the VPAC 2 receptor.…”

mentioning

confidence: 86%

Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC₂ Agonism and Glucose-Dependent Insulin Secretion

Giordanetto

Revell²,

Knerr

et al. 2013

ACS Med. Chem. Lett.

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Agonists of vasoactive intestinal peptide receptor 2 (VPAC 2 ) stimulate glucose-dependent insulin secretion, making them attractive candidates for the treatment of hyperglycaemia and type-II diabetes. Vasoactive intestinal peptide (VIP) is an endogenous peptide hormone that potently agonizes VPAC 2 . However, VIP has a short serum half-life and poor pharmacokinetics in vivo and is susceptible to proteolytic degradation, making its development as a therapeutic agent challenging. Here, we investigated two peptide cyclization strategies, lactamisation and olefin-metathesis stapling, and their effects on VPAC 2 agonism, peptide secondary structure, protease stability, and cell membrane permeability. VIP analogues showing significantly enhanced VPAC 2 agonist potency, glucose-dependent insulin secretion activity, and increased helical content were discovered; however, neither cyclization strategy appeared to effect proteolytic stability or cell permeability of the resulting peptides.

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mentioning

confidence: 86%

Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC₂ Agonism and Glucose-Dependent Insulin Secretion

Giordanetto

Revell²,

Knerr

et al. 2013

ACS Med. Chem. Lett.

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“…Bad is the BH3-only protein that has been most directly linked to glucose metabolism (Danial, 2008). Baddeficient murine hepatocytes deprived of glucose are strikingly protected from cell death compared with their normal counterparts (Danial et al, 2003).…”

Section: Regulation Of Tumor Cell Death By the Glycolytic Metabolism mentioning

confidence: 99%

“…These mice display glucose intolerance and a defect in insulin production by pancreatic islets (Danial et al, 2008). Intriguingly, Bad BH3 motive, which regulates cell death induced by some stimuli, was shown to be required for the activity of the hexokinase.…”

Section: Regulation Of Tumor Cell Death By the Glycolytic Metabolism mentioning

confidence: 99%

Sugar-free approaches to cancer cell killing

et al. 2010

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Tumors show an increased rate of glucose uptake and utilization. For this reason, glucose analogs are used to visualize tumors by the positron emission tomography technique, and inhibitors of glycolytic metabolism are being tested in clinical trials. Upregulation of glycolysis confers several advantages to tumor cells: it promotes tumor growth and has also been shown to interfere with cell death at multiple levels. Enforcement of glycolysis inhibits apoptosis induced by cytokine deprivation. Conversely, antiglycolytic agents enhance cell death induced by radio-and chemotherapy. Synergistic effects are likely due to regulation of the apoptotic machinery, as glucose regulates activation and levels of proapoptotic BH3-only proteins such as Bim, Bad, Puma and Noxa, as well as the antiapoptotic Bcl-2 family of proteins. Moreover, inhibition of glucose metabolism sensitizes cells to death ligands. Glucose deprivation and antiglycolytic drugs induce tumor cell death, which can proceed through necrosis or through mitochondrial or caspase-8-mediated apoptosis. We will discuss how oncogenic pathways involved in metabolic stress signaling, such as p53, AMPK (adenosine monophosphate-activated protein kinase) and Akt/mTOR (mammalian target of rapamycin), influence sensitivity to inhibition of glucose metabolism. Finally, we will analyze the rationale for the use of antiglycolytic inhibitors in the clinic, either as single agents or as a part of combination therapies.

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“…Significantly, Bad is not only a proapoptotic protein but also exhibits progrowth/ survival roles in metabolism, autophagy and the cell cycle (Zinkel et al, 2006;Danial, 2008;Danial et al, 2008). Bad overexpression stimulates proliferation, anchorage-independent growth and tumour growth in rodent fibroblasts and prostate cancer cell lines (Chattopadhyay et al, 2001;Smith et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Upregulation of Bad in some cancer cells (Kitada et al, 1998;Andreeff et al, 1999) could also be an indication of Bad proliferative activity, although it may also be a consequence of oncogene-activated death signals that are stimulated in cancer cells (Letai, 2008). In addition, in liver and pancreatic cells, Bad can also directly increase metabolism by stimulating the glycolytic enzyme glucokinase (GK-Hexokinase IV; Danial et al, 2003Danial et al, , 2008, although glucokinase expression is cell restricted (Matschinsky and Ellerman, 1968) and is not expressed in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

The BH3-only protein Bad confers breast cancer taxane sensitivity through a nonapoptotic mechanism

et al. 2010

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Dual role of proapoptotic BAD in insulin secretion and beta cell survival

Cited by 292 publications

References 53 publications

Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC₂ Agonism and Glucose-Dependent Insulin Secretion

Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC₂ Agonism and Glucose-Dependent Insulin Secretion

Sugar-free approaches to cancer cell killing

The BH3-only protein Bad confers breast cancer taxane sensitivity through a nonapoptotic mechanism

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Dual role of proapoptotic BAD in insulin secretion and beta cell survival

Cited by 292 publications

References 53 publications

Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC2 Agonism and Glucose-Dependent Insulin Secretion

Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC2 Agonism and Glucose-Dependent Insulin Secretion

Sugar-free approaches to cancer cell killing

The BH3-only protein Bad confers breast cancer taxane sensitivity through a nonapoptotic mechanism

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Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC₂ Agonism and Glucose-Dependent Insulin Secretion

Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC₂ Agonism and Glucose-Dependent Insulin Secretion