通过结合辅因子调节 TP53 活性
中文名称
通路描述
TP53 与各种转录辅因子的结合可促进、抑制或提供特异性，分别指向细胞周期停滞基因的转录或细胞死亡基因的转录。例如，锌指蛋白 ZNF385A (HZF) 作为 TP53 的转录靶标，刺激细胞周期停滞基因（如 CDKN1A）的转录。POU4F1 (BRN3A) 与 TP53 结合可刺激细胞周期停滞基因的转录同时抑制促凋亡基因的转录。ASPP 家族蛋白 PPP1R13B (ASPP1) 或 TP53BP2 (ASPP2) 与 TP53 结合可刺激促凋亡 TP53 靶基因的转录。ASPP 家族成员 PPP1R13L (iASSP) 通过干扰促性 ASPP 与 TP53 的结合而抑制 TP53 介导的促凋亡基因激活。TP53 与 POU4F2 (BRN3B) 或 hCAS/CSE1L 结合也能刺激促凋亡基因的转录。此外，辅因子与 TP53 的结合还可影响蛋白稳定性，例如 PHF20 结合 TP53 在赖氨酸残基 K370 和 K382 上的二甲基化形式，干扰 MDM2 结合，从而延长 TP53 半衰期。长非编码 RNA 也可参与 p53 依赖性转录反应。关于该主题的综述请参见 Espinosa 2008, Beckerman and Prives 2010, Murray-Zmijewski et al. 2008, An et al. 2004 和 Barsotti and Prives 2010。
英文描述
Mitochondrial unfolded protein response (UPRmt) Misfolded proteins in mitochondria activate the mitochondrial unfolded protein response (mtUPR), a program of gene expression that increases capacities for protein folding and protein degradation within the mitochondria (Zhao et al. 2002, Aldridge et al. 2007, reviewed in Cilleros-Holgado et al. 2023). Four interrelated pathways that regulate the mtUPR have been delineated: activation of Heat Shock Factor 1 (HSF1) by dissociation from HSPA1A,B (HSP70) (Sutandy et al. 2023), enhanced translocation of ATF5 to the nucleus (Fiorese et al. 2016), activation of the estrogen receptor alpha (ESR1) by phosphorylation, and activation of FOXO3 by deacetylation (reviewed in Kenny and Germain 2017, Munch 2018, Shpilka and Haynes 2018, Zhou et al. 2022).
The mtUPR appears to be initiated by the accumulation of reactive oxygen species (ROS) and mitochondrial precursor proteins in the cytosol (Sutandy et al. 2023). The ROS oxidize cysteine residues on DNAJA1, causing DNAJA1 to displace HSF1 from the chaperone HSPA1A,B (HSP70). HSF1 then transits to the nucleus, trimerizes, and activates expression of genes encoding chaperones (Sutandy et al. 2023).
The transcription factor ATF5, which is normally imported into mitochondria, instead accumulates in the cytosol and transits to the nucleus (Fiorese et al. 2016), where it acts with HSF1 to increase expression of chaperone genes (Fiorese et al. 2016, Sutandy et al. 2023). ATF5 may act downstream of HSF1, as ATF5 is not required to initiate the mtUPR (Sutandy et al. 2023).
ROS also activate the protein kinase AKT1 (PKB) (Papa and Germain 2011), which phosphorylates the estrogen receptor ESR1 (Campbell et al. 2001, Papa and Germain 2011). Phosphorylated ESR1 transits to the nucleus and, independently of estrogen, activates the expression of HTRA2 (OMI), NRF1, and other genes involved in mitochondrial homeostasis as part of the mitochondrial unfolded response (Papa and Germain 2011).
Through an uncharacterized mechanism, ROS cause increased expression of the deacetylase SIRT3, which directly or indirectly causes the deacetylation of the transcription factor FOXO3. Deacetylated FOXO3 in the nucleus increases expression of the antioxidant enzymes mitochondrial superoxide dismutase (SOD2, MnSOD) and peroxisomal catalase (CAT) in the mitochondrial unfolded response (Papa and Germain 2014).
Though ATF4 and CHOP are also key regulators of the mtUPR (Zhao et al. 2002, Quiros et al. 2017), the mechanisms that activate them in response to unfolded protein are not well characterized and may involve the phosphorylation of the EIF2S1 subunit of the translation factor eIF2alpha; however, none of the four known EIF2S1 kinases (GCN2, HRI, PERK, and PKR) are required for activation of CHOP (Munch and Harper 2016).
The mtUPR appears to be initiated by the accumulation of reactive oxygen species (ROS) and mitochondrial precursor proteins in the cytosol (Sutandy et al. 2023). The ROS oxidize cysteine residues on DNAJA1, causing DNAJA1 to displace HSF1 from the chaperone HSPA1A,B (HSP70). HSF1 then transits to the nucleus, trimerizes, and activates expression of genes encoding chaperones (Sutandy et al. 2023).
The transcription factor ATF5, which is normally imported into mitochondria, instead accumulates in the cytosol and transits to the nucleus (Fiorese et al. 2016), where it acts with HSF1 to increase expression of chaperone genes (Fiorese et al. 2016, Sutandy et al. 2023). ATF5 may act downstream of HSF1, as ATF5 is not required to initiate the mtUPR (Sutandy et al. 2023).
ROS also activate the protein kinase AKT1 (PKB) (Papa and Germain 2011), which phosphorylates the estrogen receptor ESR1 (Campbell et al. 2001, Papa and Germain 2011). Phosphorylated ESR1 transits to the nucleus and, independently of estrogen, activates the expression of HTRA2 (OMI), NRF1, and other genes involved in mitochondrial homeostasis as part of the mitochondrial unfolded response (Papa and Germain 2011).
Through an uncharacterized mechanism, ROS cause increased expression of the deacetylase SIRT3, which directly or indirectly causes the deacetylation of the transcription factor FOXO3. Deacetylated FOXO3 in the nucleus increases expression of the antioxidant enzymes mitochondrial superoxide dismutase (SOD2, MnSOD) and peroxisomal catalase (CAT) in the mitochondrial unfolded response (Papa and Germain 2014).
Though ATF4 and CHOP are also key regulators of the mtUPR (Zhao et al. 2002, Quiros et al. 2017), the mechanisms that activate them in response to unfolded protein are not well characterized and may involve the phosphorylation of the EIF2S1 subunit of the translation factor eIF2alpha; however, none of the four known EIF2S1 kinases (GCN2, HRI, PERK, and PKR) are required for activation of CHOP (Munch and Harper 2016).
所含基因
19 个基因