Inhibition of Caspases Rescues Brown Adipocytes from Apoptosis Downregulating BCL-XS and Upregulating BCL-2 Gene Expression

Navarro, Paloma; Valverde, Ángela M.; Conejo, Rubén; Benito, Manuel; Lorenzo, Margarita

doi:10.1006/excr.1998.4307

Cited by 6 publications

(3 citation statements)

References 27 publications

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“…Among these proapoptotic ERK mechanisms, the relationship with reactive oxygen species (ROS)-mediated cell death induction, which is explained by ROS-induced ERK activation after cell death, has been most frequently mentioned. 18, 19, 20, 21, 22, 24, 25, 26, 27, 28, 29, 30, 31 However, in the present model, neither ROS production (Supplementary Figure 5a) nor the inhibitory effect of antioxidants in CB irradiation-induced glioma cell death was confirmed (Supplementary Figure 5b). Thus, unlike cell death induced by other high-dose DNA damage stresses, which induce ROS-dependent cell death, it was suggested that gliomas do not produce ROS even after a maximum clinical dose of CB irradiation, which may be related to the refractory nature against standard radiotherapy.…”

Section: Discussioncontrasting

confidence: 68%

“…First, these pan-caspase inhibitors block an unknown caspase(s) that works upstream of the mitochondria in multiple cell death-inducing systems of U251 cells, and second, these inhibitors work by an unexpected mechanism other than caspase inhibition in U251 cells, as indicated in previous reports. 26, 27, 28 Neither of these potential mechanisms was demonstrated in the present experimental system, but there is little doubt that major known caspases are not involved in the regulation of CB irradiation-induced glioma cell death upstream of the mitochondria in T98G or U251 cells. Another interesting finding about the caspase-activation mechanism in this study was caspase-8 activation downstream of the mitochondria.…”

Section: Discussionmentioning

confidence: 59%

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MEK–ERK-dependent multiple caspase activation by mitochondrial proapoptotic Bcl-2 family proteins is essential for heavy ion irradiation-induced glioma cell death

et al. 2010

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Recently developed heavy ion irradiation therapy using a carbon beam (CB) against systemic malignancy has numerous advantages. However, the clinical results of CB therapy against glioblastoma still have room for improvement. Therefore, we tried to clarify the molecular mechanism of CB-induced glioma cell death. T98G and U251 human glioblastoma cell lines were irradiated by CB, and caspase-dependent apoptosis was induced in both cell lines in a dose-dependent manner. Knockdown of Bax (BCL-2-associated X protein) and Bak (BCL-2-associated killer) and overexpression of Bcl-2 or Bcl-xl (B-cell lymphoma-extra large) showed the involvement of Bcl-2 family proteins upstream of caspase activation, including caspase-8, in CB-induced glioma cell death. We also detected the activation of extracellular signal-regulated kinase (ERK) and the knockdown of ERK regulator mitogen-activated protein kinase kinase (MEK)1/2 or overexpression of a dominant-negative (DN) ERK inhibited CB-induced glioma cell death upstream of the mitochondria. In addition, application of MEK-specific inhibitors for defined periods showed that the recovery of activation of ERK between 2 and 36 h after irradiation is essential for CB-induced glioma cell death. Furthermore, MEK inhibitors or overexpression of a DN ERK failed to significantly inhibit X-ray-induced T98G and U251 cell death. These results suggested that the MEK–ERK cascade has a crucial role in CB-induced glioma cell death, which is known to have a limited contribution to X-ray-induced glioma cell death.

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Section: Discussioncontrasting

confidence: 68%

Section: Discussionmentioning

confidence: 59%

MEK–ERK-dependent multiple caspase activation by mitochondrial proapoptotic Bcl-2 family proteins is essential for heavy ion irradiation-induced glioma cell death

et al. 2010

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“…A loss of Bcl-2 expression is associated with apoptotic death of brown adipocytes while upregulation is associated with prevention of apoptosis. 25 Brown adipocytes and pancreatic b-cells of obese (fa/fa) rats were found to have lower Bcl-2 or Bcl-2/Bax mRNA and protein ratios than those of their lean littermates. 26,27 Fatty acids can induce apoptosis of b-cells in culture, but a leptindependent maintenance of Bcl-2 expression has been found to protect against this.…”

Section: Introductionmentioning

confidence: 97%

Adipose tissue cellularity and apoptosis after intracerebroventricular injections of leptin and 21 days of recovery in rats

et al. 2003

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OBJECTIVE:To determine the effect of leptin and post-treatment recovery on adipose tissue cellularity and apoptosis. In addition, to investigate whether Bcl-2 and/or Bax is involved in the mechanism of leptin-induced adipose tissue apoptosis. DESIGN: A total of 24 adult male Sprague-Dawley rats were injected i.c.v. with either 10 mg mouse leptin or 10 ml vehicle once per day for 4 days. At 24 h after the last injection, one group was killed while the other was monitored for 21 days. MEASUREMENTS: DNA fragmentation and Bcl-2 and Bax protein levels were determined in inguinal (ING), epididymal (EPI) and retroperitoneal (RP) white adipose tissues and the interscapular brown adipose tissue (BAT). Cellularity was determined in ING and EPI. RESULTS: Leptin significantly reduced the masses of all white fat pads [RP>ING>EPI] but not BAT. Cell volume was significantly reduced in EPI and ING. Only ING had a significantly reduced cell number from leptin treatment plus exhibited apoptosis by increased DNA fragmentation and DNA laddering, and upregulation of pro-apoptosis Bax protein. The other fat pads exhibited a general trend to increase the Bcl-2/Bax ratio. Recovery allowed for normalization of white fat pad mass, cell number and cell volume; however, BAT mass increased 42% over control. After recovery, apoptosis was not detected, Bcl-2 protein had increased in ING, and the Bcl-2/Bax ratio had risen overall. CONCLUSIONS: Central administration of mouse leptin in the rat targets white fat depots individually to reduce mass by a reduction in cell volume plus adipocyte deletion in, at least, the ING fat pad by Bax-mediated apoptosis. Even after a dramatic loss in adipose tissue mass and change in cellularity, the rat demonstrates a resilient return to control levels together with an increase in factors that prevent adipocyte loss.

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Role of Bcl-2 family of proteins in mediating apoptotic death of PC12 cells exposed to oxygen and glucose deprivation

Koubi¹,

Jiang

Zhang³

et al. 2005

Neurochemistry International

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Inhibition of Caspases Rescues Brown Adipocytes from Apoptosis Downregulating BCL-XS and Upregulating BCL-2 Gene Expression

Cited by 6 publications

References 27 publications

MEK–ERK-dependent multiple caspase activation by mitochondrial proapoptotic Bcl-2 family proteins is essential for heavy ion irradiation-induced glioma cell death

MEK–ERK-dependent multiple caspase activation by mitochondrial proapoptotic Bcl-2 family proteins is essential for heavy ion irradiation-induced glioma cell death

Adipose tissue cellularity and apoptosis after intracerebroventricular injections of leptin and 21 days of recovery in rats

Role of Bcl-2 family of proteins in mediating apoptotic death of PC12 cells exposed to oxygen and glucose deprivation

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