RhoA GTPase plays a crucial role in numerous biological functions and is linked to cancer metastasis. However, the understanding of the molecular mechanism responsible for RhoA transcription is still very limited. Here we show that RhoA transcription is orchestrated by the Myc/Skp2/Miz1/p300 transcription complex. Skp2 cooperates with Myc to induce RhoA transcription by recruiting Miz1 and p300 to the RhoA promoter independently of SCF-Skp2 E3 ligase activity. Deficiency of this complex results in impairment in RhoA expression, cell migration, invasion, and breast cancer metastasis, recapitulating the phenotypes observed in RhoA knockdown, and RhoA restoration rescues the defect in cell invasion. Strikingly, the overexpression of Myc/Skp2/Miz1 complex is found in metastatic human cancers and correlated with RhoA expression. Our study provides great insight into how oncogenic Skp2 and Myc coordinate to induce RhoA transcription and establishes a novel SCF-Skp2 E3 ligase-independent function for oncogenic Skp2 in transcription and cancer metastasis.
In response to environmental cues, cells coordinate a balance between anabolic and catabolic pathways. In eukaryotes, growth factors promote anabolic processes and stimulate cell growth, proliferation, and survival through activation of the phosphoinositide 3-kinase (PI3K)-Akt pathway. Akt-mediated phosphorylation of glycogen synthase kinase-3β (GSK-3β) inhibits its enzymatic activity, thereby stimulating glycogen synthesis. We show that GSK-3β itself inhibits Akt by controlling the mammalian target of rapamycin complex 2 (mTORC2), a key activating kinase for Akt. We found that during cellular stress, GSK-3β phosphorylated the mTORC2 component rictor at serine-1235, a modification that interfered with the binding of Akt to mTORC2. The inhibitory effect of GSK-3β on mTORC2-Akt signaling and cell proliferation was eliminated by blocking phosphorylation of rictor at serine-1235. Thus, in response to cellular stress, GSK-3β restrains mTORC2-Akt signaling by specifically phosphorylating rictor, thereby balancing the activities of GSK-3β and Akt, two opposing players in glucose metabolism.
SUMMARY The Mre11/Rad50/NBS1 (MRN) complex is thought to be a critical sensor that detects damaged DNA and recruits ATM to DNA foci for activation. However, it remains to be established how the MRN complex regulates ATM recruitment to the DNA foci during DNA double-strand breaks (DSBs). Here we show that Skp2 E3 ligase is a key component for the MRN complex-mediated ATM activation in response to DSBs. Skp2 interacts with NBS1 and triggers K63-linked ubiquitination of NBS1 upon DSBs, which is critical for the interaction of NBS1 with ATM, thereby facilitating ATM recruitment to the DNA foci for activation. Finally, we show that Skp2 deficiency exhibits a defect in homologous recombination (HR) repair, thereby increasing IR sensitivity. Our results provide molecular insights into how Skp2 and the MRN complex coordinate to activate ATM, and identify Skp2-mediatetd NBS1 ubiquitination as a vital event for ATM activation in response to DNA damage.
Prostate stem cell antigen (PSCA), a member of the LY-6/Thy-1 family of glycosylphosphatidylinositol-anchored cell surface proteins, is considered to be involved in the cell-proliferation inhibition and/or cell-death induction activity. Two single nucleotide polymorphisms (SNPs) (rs2976392 and rs2294008) in the PSCA gene were recently identified as the susceptibility loci of gastric cancer, especially in diffuse type. Therefore, this study was to investigate whether these 2 SNPs were associated with the risk of gastric cancer in Chinese population. We genotyped rs2976392 and rs2294008 in PSCA in a case-control study including 1,053 incident gastric cancer patients and 1,100 cancer-free controls in a high-risk Chinese population. We found that variant genotypes of rs2976392 (GA/AA) were associated with a significantly 37% increased risk of gastric cancer (adjusted OR 51.37, 95% CI 5 1.15-1.62), compared with variant homozygote GG, and the associations were all consistently significant in both intestinal and diffuse subtypes, and among different subgroups stratified by age, sex, drinking or smoking status. Interestingly, a significant multiplicative interaction between rs2976392 (GA/AA) and alcohol drinking was detected on the development of intestinal-type gastric cancer (p 5 0.009). However, rs2294008 variant genotypes (CT/TT) were associated with a nonsignificant increased risk of gastric cancer (adjusted OR 5 1.14, 95% CI 5 0.96-1.36). A small meta-analysis including 5 case-control studies showed undoubtedly associations between PSCA rs2294008 and rs2976392 and gastric cancer risk (OR 5 1.83, 95% CI: 1.29-2.60 and OR 5 1.84, 95% CI: 1.33-2.56, respectively). These findings provide further evidence supporting that the genetic variants of PSCA gene may contribute to the gastric carcinogenesis.Approximately 40% gastric cancer cases occur in China, 1 which remains a huge burden for Chinese and is one of the key public health issues in cancer prevention and control for Chinese government. Gastric cancer, predominantly adenocarcinoma, could be further classified as intestinal and diffuse subtypes.2 Intestinal-type tumors are characterized by a corpus-dominated gastritis with gastric atrophy and intestinal metaplasia, whereas diffuse-type tumors are characterized by gastritis throughout the stomach.3 Intestinal-type tumors are found predominantly in geographic areas with a high incidence of gastric cancer, whereas diffuse-type tumors are found more uniformly throughout the world.The exact mechanism of gastric cancer development remains unclear. Although some exogenous factors, such as diet, tobacco smoke and Helicobacter pylori, have been proposed to play important role in gastric carcinogenesis, the genetic susceptibility factors may also contributed to gastric cancer development, especially to diffuse-type gastric cancer. 4,5 The prostate stem cell antigen (PSCA) gene encodes a 123-amino acid glycoprotein, which is a cell surface antigen. PSCA is highly expressed by a large proportion of human prostate tumors, incl...
DNA damage response is an important surveillance mechanism used to maintain the integrity of the human genome in response to genotoxic stress. Histone variant H2AX is a critical sensor that undergoes phosphorylation at serine 139 upon genotoxic stress, which provides a docking site to recruit the mediator of DNA damage checkpoint protein 1 (MDC1) and DNA repair protein complex to sites of DNA breaks for DNA repair. Here, we show that monoubiquitination of H2AX is induced upon DNA double strand breaks and plays a critical role in H2AX Ser-139 phosphorylation (␥-H2AX), in turn facilitating the recruitment of MDC1 to DNA damage foci. Mechanistically, we show that monoubiquitination of H2AX induced by RING finger protein 2 (RNF2) is required for the recruitment of active ataxia telangiectasia mutated to DNA damage foci, thus affecting the formation of ␥-H2AX. Importantly, a defect in monoubiquitination of H2AX profoundly enhances ionizing radiation sensitivity. Our study therefore suggests that monoubiquitination of H2AX is an important step for DNA damage response and may have important clinical implications for the treatment of cancers. DNA damage response (DDR)3 involves serial molecular events that are activated during DNA double strand breaks (DSBs) and are important for the repair of damaged DNA (1, 2). Histone variant H2AX is a central player for DDR. Upon DNA damage, H2AX is phosphorylated by ataxia telangiectasia mutated (ATM) and ATM-related kinases at serine 139, known as ␥-H2AX, which serves as a docking site to recruit the mediator of DNA damage checkpoint protein 1 (MDC1) to sites of DNA damage, named DNA damage foci (3, 4). MDC1 is then phosphorylated by ATM within the DNA damage foci and facilitates the recruitment of RING finger protein 8 (RNF8) ubiquitin ligase (E3) to the DNA damage foci (1, 2). RNF8 then recruits RING finger protein 168 (RNF168) E3 ligase to promote polyubiquitination of proteins near the DNA damage foci, in turn recruiting breast cancer 1, early onset (BRCA1)-receptor-associated protein 80 (RAP80) complex to DNA damage sites for DNA repair.
The results of this study indicate that surgical treatment improved the quality of life of patients with NSCLC spinal metastases over the nine-month assessment period. The surgery group had a better quality of life and longer survival than the non-surgery group.
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