Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.31 (AMP-activated protein kinase)
 13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we examined the effect of heat pulsing on oocyte maturation and assessed the possible role of stress-activated enzymes during heat stress-induced meiotic maturation. Denuded oocytes from immature eCG-primed mice were pulsed for 30 min at increasing temperatures from 40 degrees C to 43 degrees C in dibutyryl cAMP-containing medium and were subsequently cultured at 37 degrees C for a total incubation time of 17-18 h. Oocytes exposed to 42 degrees C showed the greatest stimulation of maturation, with no effect at 43 degrees C. A heat pulse did not compromise progression to metaphase II as observed by polar body (PB) formation. The AMP-activated protein kinase (PRKA) inhibitors compound C and Ara-A each blocked the meiosis-stimulating effects of heat. Western blots showed that acetyl-CoA carboxylase, an important substrate of PRKA, was phosphorylated in heat-treated germinal vesicle-stage oocytes, indicating activation of PRKA before maturation. The mitogen-activated protein 2 kinase (MAP2K1) inhibitor PD98059 also prevented heat-induced maturation, but this effect was unrelated to MAPK1/3 activation, which was not observed until after germinal vesicle breakdown (GVB). Phosphorylated MAPK14 was not detected in the oocyte under any experimental condition, and only high concentrations of the MAPK14 inhibitor SB203580 blocked heat-stimulated maturation, suggesting that MAPK14 is not involved in meiotic induction. MAPK8/9 was activated by heat, and the MAPK8/9 inhibitor SP600125, but not JUN N-terminal kinase I, blocked heat-induced maturation. Heat treatment transiently suppressed GVB and PB formation in spontaneously maturing oocytes by a mechanism that is apparently different from its meiosis-inducing action. Collectively, these data show that an acute heat pulse stimulates GVB in meiotically arrested oocytes and suggest that this effect is mediated through the activation of PRKA.
 ...
PMID:Meiotic induction by heat stress in mouse oocytes: involvement of AMP-activated protein kinase and MAPK family members. 1710 31

A crucial role for both insulin and mTOR in the regulation of milk protein synthesis is emerging. Bovine mammary biopsies harvested during late-pregnancy through end of subsequent lactation were used to evaluate via quantitative PCR the expression of 44 genes involved in pathways of insulin, mTOR, AMPK, and Jak2-Stat5 signalling and also glucose and amino acid (AA) transporters. We observed an increased expression during lactation of ELF5, AA and glucose transporters, insulin signaling pathway components, MAPK14, FRAP1, EIF4EBP2, GSK3A and TSC1 among mTOR signaling-related genes. Among ribosomal components RPL22 was down-regulated. The overall data support a central role of AA and glucose transporters and insulin signaling through mTOR for the regulation of protein synthesis in bovine mammary gland. Furthermore, the existence of translational competition favoring the translation of milk protein transcripts was inferred from the combined dataset.
 ...
PMID:Gene networks driving bovine mammary protein synthesis during the lactation cycle. 2169 73

Autophagy and senescence have been described as central features of cell biology, but the interplay between these mechanisms remains obscure. Using a therapeutically relevant model of DNA damage-induced senescence in human glioma cells, we demonstrated that acute treatment with temozolomide induces DNA damage, a transitory activation of PRKAA/AMPK-ULK1 and MAPK14/p38 and the sustained inhibition of AKT-MTOR. This produced a transient induction of autophagy, which was followed by senescence. However, at the single cell level, this coordinated transition was not observed, and autophagy and senescence were triggered in a very heterogeneous manner. Indeed, at a population level, autophagy was highly negatively correlated with senescence markers, while in single cells this correlation did not exist. The inhibition of autophagy triggered apoptosis and decreased senescence, while its activation increased temozolomide-induced senescence, showing that DNA damage-induced autophagy acts by suppressing apoptosis.
...
PMID:Single-cell analysis challenges the connection between autophagy and senescence induced by DNA damage. 2570 85

Prostate cancer (PCa) is the second leading cause of cancer-related death in men; however, the molecular mechanisms leading to its development and progression are not yet fully elucidated. Of note, it has been recently shown that conditional stk11 knockout mice develop atypical hyperplasia and prostate intraepithelial neoplasia (PIN). We recently reported an inverse correlation between the activity of the STK11/AMPK pathway and the MAPK/p38 cascade in HIF1A-dependent malignancies. Furthermore, MAPK/p38 overactivation was detected in benign prostate hyperplasia, PIN and PCa in mice and humans. Here we report that STK11 expression is significantly decreased in PCa compared to normal tissues. Moreover, STK11 protein levels decreased throughout prostate carcinogenesis. To gain insight into the role of STK11-MAPK/p38 activity balance in PCa, we treated PCa cell lines and primary biopsies with a well-established MAPK14-MAPK11 inhibitor (SB202190), which has been extensively used in vitro and in vivo. Our results indicate that inhibition of MAPK/p38 significantly affects PCa cell survival in an STK11-dependent manner. Indeed, we found that pharmacologic inactivation of MAPK/p38 does not affect viability of STK11-proficient PCa cells due to the triggering of the AMPK-dependent autophagic pathway, while it induces apoptosis in STK11-deficient cells irrespective of androgen receptor (AR) status. Of note, AMPK inactivation or autophagy inhibition in STK11-proficient cells sensitize SB202190-treated PCa cells to apoptosis. On the other end, reconstitution of functional STK11 in STK11-deficient PCa cells abrogates apoptosis. Collectively, our data show that STK11 is a key factor involved in the early phases of prostate carcinogenesis, and suggest that it might be used as a predictive marker of therapeutic response to MAPK/p38 inhibitors in PCa patients.
 ...
PMID:Loss of STK11 expression is an early event in prostate carcinogenesis and predicts therapeutic response to targeted therapy against MAPK/p38. 2639 55

The ataxia-telangiectasia mutated (ATM) protein kinase is best known for its critical nuclear roles in the DNA damage response (DDR), cell cycle checkpoints, and the maintenance of gene stability. In this review, we highlight the multifaceted cytoplasmic functions of ATM in autophagy. We focused on the functions of ATM in nonselective autophagy in cancer. An Oncomine database analysis showed a tight association between ATM and autophagy in various cancers. In particular, its mechanisms in nonselective autophagy, those induced by ionizing radiation (IR), are illustrated in detail and involve the MAPK14 pathway, mTOR pathway, and Beclin1/PI3KIII complexes. Recently, an increasing number of studies revealed that autophagy could also be highly selective. We additionally emphasized the novel roles of ATM in selective autophagy, including mitophagy, pexophagy, and lipophagy. The regulation of these processes mainly involves ATM-PEX5, ATM-AMPK-TSC2-mTORC1-ULK1, PPM1D-ATM-MTOR, PINK I/Parkin, and NAD+/SIRT1. We aimed to provide new perspectives on the importance of ATM in the diverse field of autophagy. The intricate regulation of ATM in autophagy still requires further investigation, which would enhance our understanding of its role in cell dynamics and homeostasis. SIGNIFICANCE OF THE STUDY: Our review highlighted the multifaceted cytoplasmic functions of ATM on autophagy. First, we focused on the functions of ATM in nonselective autophagy within cancer especially those induced by IR, involving the MAPK14 pathway, mTOR pathway, and Beclin1/PI3KIII complexes. These provided a theoretical understanding of tumour radiosensitivity and chemosensitivity. In addition, we emphasized the novel roles of ATM in selective autophagy, including mitophagy, pexophagy, and lipophagy. This review provides new perspectives on the importance of ATM in the diverse field of autophagy, which would provide more information on its role in whole cell dynamics and homeostasis.
 ...
PMID:Multifaceted roles of ATM in autophagy: From nonselective autophagy to selective autophagy. 3084 60