China
Africa
Explore chapters and articles related to this topic
Retinoic acid signaling in spermatogenesis and male (in)fertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Dario Santos, Rita Payan-Carreira
In addition to its canonical effects (gene-mediated), RA has some nongenomic (gene-independent) functions. Noncanonical retinoid signaling is independent of gene transcription mediated by RAR/RXR heterodimers (27). Some of these nongenomic effects are the result of RA binding to retinoid receptors but can often occur in the absence of retinoid receptors. RAR has also been implicated in mediating RA nongenomic actions (46). Evidence indicates that RA also utilizes other nongenomic pathways: phospholipase C-PKC, phosphatidylinositol-3-kinase (PI3 K)-Akt (47), RAF-ERK-MAPK pathway or v-src sarcoma (SRC) tyrosine kinase activation (46,48). PI3 K activates PDK1, which in turn activates Akt. This kinase mediates the mammalian target of rapamycin (mTor) activity, a serine/threonine protein kinase. mTor is the catalytic subunit of the mTORC-1 protein complex, integrating nutrient signals and mitogen promoting cell survival, growth and proliferation (49). The RA activated-dependent PI3 K/Akt pathway leads to phosphorylation of the tuberous sclerosis protein (TSC1), resulting in mTORC-1 activation. The downstream effectors of mTORC-1 are translational modulators within the protein synthesis pathway, ribosomal S6 kinase 1 (S6K1) and initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), which are stimulated by mTORC1-mediated phosphorylation, enhancers of protein synthesis, cell growth and proliferation (49). AKT also contributes to cell cycle progression and inhibition of apoptosis by increasing the expression of cyclins and antiapoptotic Bcl-2 family members, mediating hyperphosphorylation of proapoptotic BAD, leading to the mitochondrial-dependent apoptosis (intrinsic apoptosis pathway) (50). Additionally, RA activates the ERK-MAPK signaling cascade and regulates mTORC-1 activity: ERK phosphorylates and activates kinase RSK1 that in turn phosphorylates and inhibits TSC1/2, followed by increased activity of mTORC-1 (29,47).
Establishing and characterizing a novel doxorubicin-resistant acute myeloid leukaemia cell line
Published in Journal of Chemotherapy, 2023
Inês Castro, Vanessa Lopes-Rodrigues, Helena Branco, M. Helena Vasconcelos, Cristina P. R. Xavier
TSC2 (tuberous sclerosis protein complex 2) or tuberin 2 is the product of the tumour supressor gene and a negative regulator of mammalian target of rapamycin complex 1 (mTORC1) [44]. Nevertheless, the TSC1-TSC2 complex has also been implicated in cell survival responses. For instance, the reconstitution of TSC2 expression in TSC2-/- mouse embryonic fibroblasts rescued survival in an NF-kB activity-dependent manner [45]. Thus, an upregulation of TSC2 in HL60-CDR cells may also contribute to the growth of the resistant cells. Indeed, by Western Blot analysis, this protein was also detected at higher levels in the resistant cells, when compared to the parental cells (Figure 7b and c).
Targeting PRAS40: a novel therapeutic strategy for human diseases
Published in Journal of Drug Targeting, 2021
Qun Zhou, Shengsong Tang, Xianhui Zhang, Linxi Chen
mTOR exists in two forms: mTORC1 and mTORC2. Among them, mTORC1 is sensitive to rapamycin, which can regulate cell transcription, autophagy, mitochondrial function and is also involved in other cellular processes such as protein synthesis [55–57]. It has been confirmed that the proteins associated with mTORC1 include mTOR, PRAS40, raptor and mLST8, while mTORC2 include mTOR, Rictor, mLST8 and protor. It can be seen that PRAS40 is a component of mTORC1, not a component of mTORC2 [11,58]. The interaction between PRAS40 and mTORC1 could inhibit the activity of mTORC1 [5]. Many literatures have reported that PRAS40 participated in the regulation of mTORC1. The phosphorylation of PRAS40 leads to the separation of PRAS40 from mTORC1, which reduces the inhibition of mTORC1 [5]. Further study found that the dissociation of p-PRAS40 and mTORC1 may be caused by the interaction between p-PRAS40 and 14-3-3 [59]. After mTORC1 kinase is activated by upstream regulators, PRAS40 is directly phosphorylated by mTOR, which helps to alleviate PRAS40-mediated substrate competition [8]. Overexpression of PRAS40 could block the expression of mTORC1 [60]. The decrease of PRAS40 phosphorylation caused by the decrease of PKM2 activity also contributed to the inhibition of mTORC1 [61]. In astrocytes with tuberous sclerosis protein 1 (TSC1) gene knockout up-regulated by mTORC1 pathway, the transcription of PRAS40 itself is enhanced, which further indicates that mTORC1 signal can up-regulate the expression and phosphorylation level of PRAS40 [11]. Hong-Brown et al. reported that PRAS40 deletion could enhance the level of AMP-activated protein kinase (AMPK) mediated phosphorylation of TSC2, a negative regulator of mTOR, resulting in partial inhibition of the activity of mTORC1, which further shows the positive regulatory effect of PRAS40 [62].