Induction of Apoptosis in Luteinized Granulosa Cells by the MAP Kinase Kinase (MEK) Inhibitor PD98059

Oliver, Rush H.; Khan, Shah M.; Leung, Benjamin S.; Yeh, John

doi:10.1006/bbrc.1999.1301

Cited by 26 publications

(15 citation statements)

References 29 publications

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“…Because Erk-1 and -2 are phosphorylated by MEK 1/2 [36,37], the PD98059 study implicates the activation of these MAP kinases in the apoptotic cascade. The concept that SIGCs undergo apoptosis through a MAP kinase-dependent mechanism may appear to be in opposition to our own study [14] as well as others [38,39]. The studies by Oliver et al [38] demonstrate that complete inhibition of the Erk pathway by a 60-min pretreatment of human granulosa/luteal cells with a high concentration of PD98059 (100 M) results in apoptosis.…”

Section: Discussioncontrasting

confidence: 79%

“…The concept that SIGCs undergo apoptosis through a MAP kinase-dependent mechanism may appear to be in opposition to our own study [14] as well as others [38,39]. The studies by Oliver et al [38] demonstrate that complete inhibition of the Erk pathway by a 60-min pretreatment of human granulosa/luteal cells with a high concentration of PD98059 (100 M) results in apoptosis. The study of Gebauer and associates [39] reveals that the activity of members of the Ras-MEK-Erk pathway is reduced in atretic follicles.…”

Section: Discussioncontrasting

confidence: 79%

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Expression Pattern and Role of a 60-Kilodalton Progesterone Binding Protein in Regulating Granulosa Cell Apoptosis: Involvement of the Mitogen-Activated Protein Kinase Cascade1

Peluso¹,

Bremner

Fernández

et al. 2003

Biology of Reproduction

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Progesterone (P4) inhibits both granulosa cells and spontaneously immortalized granulosa cells (SIGCs) from undergoing apoptosis. P4 does so through a plasma membrane-initiated event. It appears that P4's membrane-initiated actions are mediated by a 60-kDa P4 binding protein (P4BP), which is detected by an antibody directed against the ligand binding domain of the nuclear P4 receptor (i.e., C-262). Immunohistochemical analysis revealed that a C-262-detectable protein was first observed in the periphery of a few granulosa cells within early antral-stage follicles. In nonatretic antral follicles, this protein was detected at the periphery of virtually all granulosa cells. In contrast, granulosa cells of atretic follicles lost the distinct peripheral localization of this C-262-detectable protein. This reduction in the membrane localization was also observed by Western blot analysis. To assess the temporal changes in this 60-kDa P4BP during apoptosis, studies were conducted using SIGCs. That this 60-kDa protein is important in mediating P4's action was confirmed by the observation that C-262 but not IgG attenuated P4's antiapoptotic action. Interestingly, the membrane localization of this 60-kDa P4BP was maintained but the ability of P4 to prevent apoptosis was lost within 20 min of initiating the apoptotic cascade. In addition, Erk-1 and -2 phosphorylation (i.e., activity) increased within 20 min of P4 withdrawal. Further, P4 suppressed the increase in the Erk-1 phosphorylation if administered within 5 but not 20 min of initiating the apoptotic cascade. Moreover, the mitogen-activated protein kinase kinase (MEK) inhibitor, PD98059, reduced the percentage of SIGCs undergoing apoptosis in the absence of P4. Because MEK phosphorylates Erk, these observations suggests that 1) the increase in Erk-1 activity is an important part of the apoptotic cascade, 2) P4 promotes granulosa cell viability by modulating the activity of Erk-1, and 3) P4 becomes "uncoupled" from its antiapoptotic signal transduction mechanism within 20 min of initiating apoptosis, even though the membrane localization of the 60-kDa P4BP is maintained.

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Section: Discussioncontrasting

confidence: 79%

Section: Discussioncontrasting

confidence: 79%

Expression Pattern and Role of a 60-Kilodalton Progesterone Binding Protein in Regulating Granulosa Cell Apoptosis: Involvement of the Mitogen-Activated Protein Kinase Cascade1

Peluso¹,

Bremner

Fernández

et al. 2003

Biology of Reproduction

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“…Targets of Akt related to apoptosis include BAD (25,28), human caspase-9 (14), forkhead transcriptional factors (6,9,46,66), NF-B (64,68), glycogen synthase kinase 3b (21), and CREB (30). ERK1/2 has also been shown to have significant survival functions in some cell types (7,32,33,63). The mechanism by which ERK1/2 can function to protect cells from apoptosis is possibly by phosphorylating BAD and activating Bcl-XL and Bcl-2 (39,71).…”

Section: Discussionmentioning

confidence: 99%

“…PI3K and ERK1/2 MAPK are signaling molecules on two major downstream pathways initiated by the activation of EGFR (11). Akt (also named protein kinase B [PKB]), which is the downstream effector of PI3K, and ERK1/2 have been well recognized as two major survival factors against apoptosis (3,7,31,32,33,47,63,69,91). Under stress conditions, PI3K and its putative effector Akt/PKB is down regulated (56,92,93), and cells normally show an inactivation of ERK1/2 with activation of JNK and p38 (5).…”

mentioning

confidence: 99%

E5 Protein of Human Papillomavirus Type 16 Protects Human Foreskin Keratinocytes from UV B-Irradiation-Induced Apoptosis

Zhang

Spandau²,

Roman

2002

J Virol

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The human papillomavirus type 16 (HPV16) E5 protein associates with the epidermal growth factor receptor (EGFR) and enhances the activation of the EGFR after stimulation by EGF in human keratinocytes. Phosphatidylinositol 3-kinase (PI3K) and ERK1/2 mitogen-activated protein kinase (ERK1/2 MAPK), two signal molecules downstream of the EGFR, have been recognized as participants in two survival signal pathways in response to stress. The fact that E5 can enhance EGFR activation suggests that E5 might act as a survival factor. To test this hypothesis, the apoptotic response of UV B-irradiated primary keratinocytes infected with either control retrovirus, LXSN, or HPV16 E5-expressing recombinant retrovirus was quantitated. Under the same conditions, LXSN-infected cells showed extensive apoptosis, while E5-expressing cells demonstrated a significant reduction in UV B-irradiation-induced apoptosis. The E5-mediated protection against apoptosis was blocked by wortmannin and PD98059, specific inhibitors of the PI3K and ERK1/2 MAPK pathways, respectively, suggesting that the PI3K and ERK1/2 MAPK pathways are involved in this process. Western blot analysis showed that Akt (also named protein kinase B), which is a downstream effector of PI3K, and ERK1/2 MAPK were activated by EGF. When cells were stimulated by EGF and irradiated by UV B, the levels of phospho-Akt and phospho-ERK1/2 activated by EGF in E5-expressing cells were about twofold greater than those in LXSN-infected cells. Two other UV-activated stress pathways, p38 and JNK, were activated to the same level during UV B irradiation in both LXSN-infected cells and E5-expressing cells, indicating that E5 protein did not affect these two pathways. After UV B irradiation, p53 was activated in both LXSN-infected cells and E5-expressing cells, and cell cycle analysis showed that nearly all cells in both cell populations were growth arrested. These data suggest that unlike HPV16 E6, which blocks apoptosis by inactivation of p53, HPV16 E5 protects cells from apoptosis by enhancing the PI3K-Akt and ERK1/2 MAPK signal pathways.

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“…These results suggest that EGF may be another activator of the Stat3 pathway in granulosa cells. Interestingly, EGF is known to control the initial growth of granulosa cells (Driancourt & Thuel 1998), apoptosis (Oliver et al 1999), and the initiation of steroidogenesis (Li et al 1995, Hernandez & Bahr 2003. The regulation of granulosa cell function by EGF was previously shown to be mediated via the MAP kinases pathway (Keel et al 1995, Keel & Davis 1999.…”

Section: Discussionmentioning

confidence: 99%

Cloning of porcine signal transducer and activator of transcription 3 cDNA and its expression in reproductive tissues

Wen¹,

Craig²,

Dyce³

et al. 2006

Reproduction

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The signal transducer and activator of transcription 3 (Stat3) protein is a member of the Stat family that has a variety of biological functions including cell growth, anti-apoptosis, and cell motility, depending on the cell type and stimulus. Recent studies have suggested that Stat3 plays an important role in embryo development. Although the Stat3 gene has been cloned in humans, mice, cow, and rats, its sequence in pigs is unknown. In the present study, the 2476 bp Stat3 cDNA was cloned using real time reverse transcriptase (RT)-PCR. Comparison of sequences across species revealed that the porcine Stat3 cDNA is 93 and 90% homologous to human and mouse respectively. To study the expression pattern of Stat3, RNA and protein were isolated from heart, lung, kidney, ovary, oviduct, and uterus tissues. RT-PCR and western blot indicated that Stat3 is expressed in all the tissues tested, and the level of expression is relatively high in tissues from the reproductive system. In addition, immunohistochemistry studies suggested that the Stat3 protein was present in the oocyte, granulosa, theca, and interstitial cells of the ovary, the mucosal folds in the oviduct, and both the epithelium and stromal layers in the endometrium. To study whether Stat3 is functional in responding to growth factor stimulation in the ovary, granulosa cells were isolated from large follicles (O3 mm) and cultured in the presence of epidermal growth factor (EGF; 10 ng/ml) for 5, 10, 15, 30, and 60 min, following which western blots were performed using an antibody against the phosphorylated Stat3. Phosphorylated Stat3 was upregulated following 5 min of EGF challenge and was sustained during the 15-min stimulation, and decreased back to the control level following 60-min stimulation. The translocation of phosphorylated Stat3 from cytoplasm to nucleus following stimulation of EGF was also detected via immunocytochemistry. Our data suggests that Stat3 may play a role in porcine ovarian function.

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Induction of Apoptosis in Luteinized Granulosa Cells by the MAP Kinase Kinase (MEK) Inhibitor PD98059

Cited by 26 publications

References 29 publications

Expression Pattern and Role of a 60-Kilodalton Progesterone Binding Protein in Regulating Granulosa Cell Apoptosis: Involvement of the Mitogen-Activated Protein Kinase Cascade1

Expression Pattern and Role of a 60-Kilodalton Progesterone Binding Protein in Regulating Granulosa Cell Apoptosis: Involvement of the Mitogen-Activated Protein Kinase Cascade1

E5 Protein of Human Papillomavirus Type 16 Protects Human Foreskin Keratinocytes from UV B-Irradiation-Induced Apoptosis

Cloning of porcine signal transducer and activator of transcription 3 cDNA and its expression in reproductive tissues

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