NCBI Summary:
The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. This kinase is activated by various environmental stresses and proinflammatory cytokines. The activation requires its phosphorylation by MAP kinase kinases (MKKs), or its autophosphorylation triggered by the interaction of MAP3K7IP1/TAB1 protein with this kinase. The substrates of this kinase include transcription regulator ATF2, MEF2C, and MAX, cell cycle regulator CDC25B, and tumor suppressor p53, which suggest the roles of this kinase in stress related transcription and cell cycle regulation, as well as in genotoxic stress response. Four alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.
General function
Enzyme, Transferase
Comment
Cellular localization
Cytoplasmic, Nuclear
Comment
Ovarian function
Cumulus expansion, Oogenesis, Oocyte maturation
Comment
Activation of p38 MAPK During Porcine Oocyte Maturation.
Villa Diaz LG, Miyano T. .
p38 MAPK is a member of the mitogen-activated protein kinase (MAPK) family that participates in a signaling cascade in response to cytokines and stress in somatic cells. The present study was designed to investigate the expression and possible function of p38 MAPK in porcine oocytes during maturation. In immunoblots p38 MAPK was detected in oocytes and cumulus cells. Its activity was determined during oocyte maturation in vitro by the phosphorylation of its substrate, activated transcription factor 2. As ERK1/2, oocyte p38 MAPK became active around germinal vesicle breakdown (GVBD) and maintained activity until metaphase II (MII). Immunofluorescent microscopy showed phosphorylated p38 MAPK accumulated in the nucleus before GVBD and localized in the cytoplasm and around chromosomes from metaphase I (MI) to MII. In cultured cumulus-oocyte complexes, a specific inhibitor of p38 MAPK, SB203580, inhibited phosphorylation of p38 MAPK in cumulus cells and blocked both FSH-induced cumulus expansion and meiotic resumption of oocytes. During spontaneous meiotic resumption of denuded oocytes, SB203580 did not affect GVBD, but it significantly decreased the number of oocytes reaching MII and conversely increased the number of oocytes arrested at MI. These results suggest that p38 MAPK in porcine oocytes becomes active around GVBD, remains active through MI to MII, and has a role in MI-MII transition, and that cumulus p38 MAPK might be involved in FSH-induced meiotic resumption of oocytes.
Expression regulated by
Growth Factors/ cytokines
Comment
p38-mitogen-activated protein kinase stimulated steroidogenesis in granulosa cell-oocyte co-cultures: role of bone morphogenetic protein (BMP)-2 and -4. Inagaki K et al. Roles of p38-MAPK pathway in steroidogenesis were investigated using co-culture of rat granulosa cells with oocytes. Activin and FSH readily phosphorylated p38 in granulosa cells. Activin effect on p38 phosphorylation was abolished by a selective ALK-4, -5, -7 inhibitor SB431542. SB431542 decreased FSH-induced estradiol, but had no effect on progesterone production with a marginal cAMP reduction, suggesting that endogenous activin is primarily involved in estradiol synthesis. FSH-induced p38 activation was not affected either by SB431542 or follistatin, suggesting that FSH activates p38 not through the endogenous activin. BMP-2 and BMP-4 also enhanced FSH-induced p38 phosphorylation, which was augmented by oocyte action. A specific p38 inhibitor SB203580 decreased FSH-induced estradiol production. However, FSH-induced cAMP accumulation was not changed by SB203580, suggesting that p38 activation is linked to estradiol synthesis independently of cAMP. BMP-2 and BMP-4 inhibited FSH- and forskolin-induced progesterone and cAMP synthesis regardless of oocyte action. BMP-2, BMP-4 and activin increased FSH-induced estradiol production, which was enhanced in the presence of oocytes. In contrast to activin that enhanced forskolin-induced estradiol, BMP-2 and BMP-4 had no effects on forskolin-induced estradiol production, suggesting that BMP-2 and BMP-4 directly activate FSH-receptor signaling. Given that activin increased, but BMP-2 and BMP-4 decreased, FSH-induced cAMP, the effects of BMP-2 and BMP-4 on estradiol enhancement appeared to be diverged from cAMP-PKA pathway. Thus, BMP-2 and BMP-4 differentially regulate steroidogenesis by stimulating FSH-induced p38 and suppressing cAMP. The former is involved in estradiol production and enhanced by oocyte action, while the latter leads to reduction of progesterone synthesis.
Ovarian localization
Oocyte, Cumulus, Granulosa
Comment
p38a MAPK is a MTOC-associated protein regulating spindle assembly, spindle length and accurate chromosome segregation during mouse oocyte meiotic maturation. Ou XH et al. P38aMAPK (p38a) is usually activated in response to various stresses and plays a role in the inhibition of cell proliferation and tumor progression, but little is known about its roles in meiotic spindle assembly. In this study, we characterized the dynamic localization of p38a and explored its function in mouse oocyte meiotic maturation. P38a specifically colocalized with ?-tubulin and Plk1 at the center of MTOCs and spindle poles. Depletion of p38a by specific morpholino injection resulted in severely defective spindles and misaligned chromosomes probably via MK2 dephosphorylation. Notably, depletion of p38a led to significant spindle pole defects, spindle elongation, non-tethered kinetochore microtubules and increased microtubule tension. The disruption of spindle stability was coupled with decreased ?-tubulin and Plk1 at MTOCs. Overexpression of Eg5, a conserved motor protein, also caused spindle elongation and its morpholino injection almost completely rescued spindle elongation caused by p38a depletion. In addition, p38a-depletion decreased BubR1 and interfered with spindle assembly checkpoint (SAC), which resulted in aneuploid oocytes. Together, these data indicate that p38a is an important component of MTOCs, which regulates spindle assembly and spindle length, as well as stabilizes the spindle and spindle poles. Perturbed SAC and abnormal microtubule tension may be responsible for the misaligned chromosomes and high aneuploidy in p38a-depleted mouse oocytes.
....The preantral granulosa cell to cumulus cell transition in the mouse ovary: Development of competence to undergo expansion. Diaz FJ et al. The transition of preantral to antral follicles is one of the major steps in follicular development, yet little is known about the molecular and functional changes that occur as preantral granulosa cells differentiate into cumulus cells. The cumulus oophorus of large antral follicles undergoes expansion in response to the preovulatory surge of gonadotropins, but preantral granulosa cells do not. The objective of this project was to determine the molecular mechanisms underlying this differential response. Cumulus expansion in vitro requires secretion of cumulus-expansion enabling factors (CEEFs) by the oocyte and stimulation by a ligand, epidermal growth factor (EGF) or follicle-stimulating hormone (FSH). This combined stimulation results in activation of MAPKs (MAPK3/1 (formerly ERK1/2) and MAPK14 (formerly p38)) and increased Has2, Ptgs2, Tnfaip6 and Ptx3 mRNA levels, all of which are required for cumulus expansion. Only fully-grown oocytes from antral follicles were competent to enable expansion and increases in expansion-related transcripts in cumulus cells, whereas growing oocytes of preantral follicles did not. To assess the competence of preantral granulosa cells to generate responses associated with expansion, they were treated with FSH or EGF and co-cultured with fully-grown oocytes secreting CEEFs. MAPKs were activated by EGF in preantral granulosa cells to essentially the same levels as in cumulus cells. Preantral granulosa cells treated with EGF, but not those treated with FSH increased Has2, Ptgs2 and Ptx3 mRNAs to 17-96% of the levels observed in cumulus cells. In contrast, the level of Tnfaip6 mRNA was minimally stimulated in preantral granulosa cells. Therefore, preantral granulosa cells do not undergo expansion for two fundamental reasons. First, the growing oocytes of preantral follicles do not secrete active CEEFs. Second, activation of MAPKs alone in preantral granulosa cells, even in the presence of CEEFs, is not sufficient to increase the expression of essential transcripts, particularly Tnfaip6 mRNA. Thus, preantral granulosa cells differ from cumulus cells in CEEF-dependent processes downstream of the activation of MAPKs.
Follicle stages
Antral, Preovulatory
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: fertile Comment: Targeted Disruption of Mapk14 (p38MAPK{alpha}) in Granulosa Cells and Cumulus Cells Causes Cell-Specific Changes in Gene Expression Profiles that Rescue Cumulus Cell-Oocyte Complex Expansion and Maintain Fertility. Liu Z et al. MAPK14 (p38MAPKalpha) is critical for FSH and prostaglandin E (PGE)2 signaling cascades in granulosa cells (GCs) and cumulus cell-oocyte complexes (COCs) in culture, indicating that this kinase might impact follicular development and COC expansion in vivo. Because Mapk14 knockout mice are embryonic lethal, we generated GC specific Mapk14 knockout mice (Mapk14gc(-/-)) by mating Mapk14(fl/fl) and Cyp19-Cre mice. Unexpectedly, the Mapk14gc(-/-) female mice were fertile. Analyses of gene expression patterns showed that amphiregulin (Areg) and epiregulin (Ereg), two key regulators of ovulation and COC expansion, were up-regulated in the GCs but down-regulated in cumulus cells of the mutant mice in vivo. COCs from the mutant mice expanded and expressed matrix-related genes, if cultured with AREG, but not when cultured with forskolin or PGE2, the latter being a key factor regulating MAPK14 activity in cumulus cells. Conversely, when GCs from the Mapk14gc(-/-) mice were cultured with forskolin, they produced more Areg and Ereg mRNA than did wild-type GCs. These results indicate that disruption of Mapk14 selectively alters the expression of Areg and other genes in each cell type. Greater AREG and EREG produced by the GCs appears to by-pass and compensate for the critical need for MAPK14 signaling and induction of Areg/Ereg (and hence matrix genes) by PGE2 in cumulus cells of the mutant mice. In conclusion, although MAPK14 is not overtly essential for preovulatory follicle development or events associated with ovulation and luteinization in vivo, it does impact gene expression profiles.