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Mitogen-activated protein kinases in normal and (pre)neoplastic ovarian surface epithelium.

Choi KC, Auersperg N, Leung PC - Reprod. Biol. Endocrinol. (2003)

Bottom Line: Mitogen-activated protein kinases (MAPKs) are a group of serine/threonine kinases which are activated in response to a diverse array of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus.It has been demonstrated that MAPKs are activated by external stimuli including chemotherapeutic agents, growth factors and reproductive hormones in ovarian surface epithelial cells.Thus, the MAPK signaling pathway may play an important role in the regulation of proliferation, survival and apoptosis in response to these external stimuli in ovarian cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Obstetrics and Gynaecology, BC Children's and Women's Hospital, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5. kchoi@cw.bc.ca

ABSTRACT
Mitogen-activated protein kinases (MAPKs) are a group of serine/threonine kinases which are activated in response to a diverse array of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus. It has been demonstrated that MAPKs are activated by external stimuli including chemotherapeutic agents, growth factors and reproductive hormones in ovarian surface epithelial cells. Thus, the MAPK signaling pathway may play an important role in the regulation of proliferation, survival and apoptosis in response to these external stimuli in ovarian cancer. In this article, an activation of the MAPK signaling cascade by several key reproductive hormones and growth factors in epithelial ovarian cancer is reviewed.

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The MAPK signaling transduction pathways.
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Figure 1: The MAPK signaling transduction pathways.

Mentions: Mitogen-activated protein kinases (MAPKs) are a group of serine/threonine kinases which are activated in response to a diverse array of extracellular stimuli, and mediate signal transduction from the cell surface to the nucleus [1]. As illustrated in Fig. 1, three MAPK family including extracellular signal-regulated kinases (ERK1 and ERK2), c-jun terminal kinase/stress-activated protein kinases (JNK/SAPK) and p38, have been well characterized [2-4]. In addition, other MAPK family members, including ERK3, 4 and 5, four p38-like kinases and p57 MAPK have been cloned, but the biological role of these MAPKs is not well understood [2,4]. The MAPK cascade is activated via two distinct classes of cell surface receptors, receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). The signals transmitted through this cascade can cause an activation of diverse molecules which regulate cell growth, survival and differentiation. ERK1 (p44 MAPK) and ERK2 (p42 MAPK) activated by mitogenic stimuli are a group of the most extensively studied members, whereas JNK/SAPK and p38 are activated in response to stress such as heat shock, osmotic shock, cytokines, protein synthesis inhibitors, antioxidants, ultra-violet, and DNA-damaging agents [5,6]. MAPK family members are directly regulated by the kinases known as MAPK kinases (MAPKKs), which activate the MAPKs by phosphorylation of tyrosine and threonine residues [2,4,6]. At least seven different MAPKKs have been cloned and characterized [2,4]. The first MAPKKs cloned were MAPK/ERK kinase 1 and 2 (MEK 1/2), which specifically activate ERKs. MKK3 and 6 specifically activate p38, whereas MKK5 stimulates the phosphorylation of ERK5. The MKK4 and 7 are known to activate JNK. The MAPKKs are activated by a rapidly expanding group of kinases called MAPKK kinases (MAPKKKs), which activate the MAPKKs by phosphorylation of serine and threonine residues [4,6]. These include Raf-1, A-Raf, B-raf, MAPK/ERK kinase 1–4 (MEKK1-4), apoptosis-stimulating kinase-1 (ASK-1), and mixed lineage kinse-3 (MLK-3). The MAPKKKs may be activated by kinases known as MAPKKK kinases (MAPKKKKs), one of which is p21-activated kinase (PAK). In addition to these kinases, low molecular weight GTP-binding (LMWG) proteins regulate the activity of MAPKKKs and MAPKKKKs [2,4]. There are several different families of LMWG proteins, two of which include the Ras (N-Ras, K-Ras, and H-Ras) and Rho (Rac 1, 2 and 3, Cdc42 and Rho A, B and C) families. The activated MAPKs phosphorylate a large number of both cytoplasmic and nuclear proteins, exerting their specific functions. For example, activated ERK1/2 phosphorylate ternary complex factor (TCF) proteins such as Elk-1 and SAP-1, which form transcriptional complexes with serum response factor (SRF) in the promoter region of early response genes (e.g. c-fos, egr-1, junB) and thereby regulate their expression [7]. As shown in Fig. 1, many of these nuclear proteins, as a result of their ability to modulate expression of other proteins, are potential candidates for critical factors involved in the cellular response to stimuli.


Mitogen-activated protein kinases in normal and (pre)neoplastic ovarian surface epithelium.

Choi KC, Auersperg N, Leung PC - Reprod. Biol. Endocrinol. (2003)

The MAPK signaling transduction pathways.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC239898&req=5

Figure 1: The MAPK signaling transduction pathways.
Mentions: Mitogen-activated protein kinases (MAPKs) are a group of serine/threonine kinases which are activated in response to a diverse array of extracellular stimuli, and mediate signal transduction from the cell surface to the nucleus [1]. As illustrated in Fig. 1, three MAPK family including extracellular signal-regulated kinases (ERK1 and ERK2), c-jun terminal kinase/stress-activated protein kinases (JNK/SAPK) and p38, have been well characterized [2-4]. In addition, other MAPK family members, including ERK3, 4 and 5, four p38-like kinases and p57 MAPK have been cloned, but the biological role of these MAPKs is not well understood [2,4]. The MAPK cascade is activated via two distinct classes of cell surface receptors, receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). The signals transmitted through this cascade can cause an activation of diverse molecules which regulate cell growth, survival and differentiation. ERK1 (p44 MAPK) and ERK2 (p42 MAPK) activated by mitogenic stimuli are a group of the most extensively studied members, whereas JNK/SAPK and p38 are activated in response to stress such as heat shock, osmotic shock, cytokines, protein synthesis inhibitors, antioxidants, ultra-violet, and DNA-damaging agents [5,6]. MAPK family members are directly regulated by the kinases known as MAPK kinases (MAPKKs), which activate the MAPKs by phosphorylation of tyrosine and threonine residues [2,4,6]. At least seven different MAPKKs have been cloned and characterized [2,4]. The first MAPKKs cloned were MAPK/ERK kinase 1 and 2 (MEK 1/2), which specifically activate ERKs. MKK3 and 6 specifically activate p38, whereas MKK5 stimulates the phosphorylation of ERK5. The MKK4 and 7 are known to activate JNK. The MAPKKs are activated by a rapidly expanding group of kinases called MAPKK kinases (MAPKKKs), which activate the MAPKKs by phosphorylation of serine and threonine residues [4,6]. These include Raf-1, A-Raf, B-raf, MAPK/ERK kinase 1–4 (MEKK1-4), apoptosis-stimulating kinase-1 (ASK-1), and mixed lineage kinse-3 (MLK-3). The MAPKKKs may be activated by kinases known as MAPKKK kinases (MAPKKKKs), one of which is p21-activated kinase (PAK). In addition to these kinases, low molecular weight GTP-binding (LMWG) proteins regulate the activity of MAPKKKs and MAPKKKKs [2,4]. There are several different families of LMWG proteins, two of which include the Ras (N-Ras, K-Ras, and H-Ras) and Rho (Rac 1, 2 and 3, Cdc42 and Rho A, B and C) families. The activated MAPKs phosphorylate a large number of both cytoplasmic and nuclear proteins, exerting their specific functions. For example, activated ERK1/2 phosphorylate ternary complex factor (TCF) proteins such as Elk-1 and SAP-1, which form transcriptional complexes with serum response factor (SRF) in the promoter region of early response genes (e.g. c-fos, egr-1, junB) and thereby regulate their expression [7]. As shown in Fig. 1, many of these nuclear proteins, as a result of their ability to modulate expression of other proteins, are potential candidates for critical factors involved in the cellular response to stimuli.

Bottom Line: Mitogen-activated protein kinases (MAPKs) are a group of serine/threonine kinases which are activated in response to a diverse array of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus.It has been demonstrated that MAPKs are activated by external stimuli including chemotherapeutic agents, growth factors and reproductive hormones in ovarian surface epithelial cells.Thus, the MAPK signaling pathway may play an important role in the regulation of proliferation, survival and apoptosis in response to these external stimuli in ovarian cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Obstetrics and Gynaecology, BC Children's and Women's Hospital, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5. kchoi@cw.bc.ca

ABSTRACT
Mitogen-activated protein kinases (MAPKs) are a group of serine/threonine kinases which are activated in response to a diverse array of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus. It has been demonstrated that MAPKs are activated by external stimuli including chemotherapeutic agents, growth factors and reproductive hormones in ovarian surface epithelial cells. Thus, the MAPK signaling pathway may play an important role in the regulation of proliferation, survival and apoptosis in response to these external stimuli in ovarian cancer. In this article, an activation of the MAPK signaling cascade by several key reproductive hormones and growth factors in epithelial ovarian cancer is reviewed.

Show MeSH
Related in: MedlinePlus