Pregnancy outcome and follow-up of offspring of donor oocytes recipient from PCOS patients.

BACKGROUND: The use of donated oocytes (DO) for in vitro fertilization(IVF) treatment in patients with infertility is generally recognized, and females with polycystic ovarian syndrome (PCOS) can participate in oocyte donation programs as donor patients. However, the pregnancy outcomes and offspring follow-up in patients with PCOS as the recipients are unclear. This study was to compare the pregnancy outcomes and follow-up of offspring in PCOS and non-PCOS receptor. METHODS: This was a retrospective cohort study of 62 patients undergoing the oocyte reception program were separated into 2 groups: Group I, PCOS oocyte recipients (n = 30); Group II, non-PCOS recipients (n = 32). Medical records were reviewed, and rates of fertilization, cleavage, high-quality embryos and blastocysts were compared between PCOS and non-PCOS groups. Rates of implantation, pregnancy, ectopic pregnancy, early abortion, multiple pregnancies, and offspring outcomes were calculated using the first single vitrified-warmed blastocyst transfer (SVBT) analysis between the groups. RESULTS: The average recipient age and body mass index (BMI) of PCOS and non-PCOS patients was (36.3 ± 2.6 vs. 36.2 ± 2.8, and 23.4 ± 3.9 vs. 23.7 ± 4.0), respectively (P > 0.05). The fertilization, cleavage, high-quality embryos and blastocyst rates were not significantly different between the PCOS and non-PCOS groups. Rates of implantation, pregnancy, ectopic pregnancy, early abortion, and multiple pregnancies were not significantly different in SVBT between the PCOS and non-PCOS groups. The incidence of complications, such as pre-eclampsia or gestational diabetes, between PCOS and non-PCOS groups was similar (11.8% vs.11.1%, 5.9% vs.5.5%; P > 0.05). Preterm births were also similar (11.8% vs.16.7%, P > 0.05). Donor oocytes are more likely to be delivered via cesarean Sect. (80.0% vs. 86.7%: P > 0.05). The mean gestational age, birth weight, and height were comparable between the 2 groups during full-term delivery. CONCLUSION: There was no difference in the pregnancy outcomes and follow-up of the offspring between the PCOS and non-PCOS groups.

Lower growth arrest-specific 5 level in endometrium is related to endometriosis via promoting cell proliferation and angiogenesis.

Long noncoding RNAs are a group of more than 200 nt, nonprotein coding RNAs, some of which are dysregulated in many pathophysiological processes including endometriosis. This study aims to clarify the roles of dysregulated growth arrest-specific 5 (GAS5) in patients with endometriosis, and unveil the underlying mechanisms. We obtained endometrium samples from 37 patients with endometriosis and 23 controls without endometriosis. Primary endometrial stromal cells (ESCs) and endothelial cells were separated from the endometrium. Levels of GAS5 were quantified using quantitative real-time polymerase chain reaction, and levels of p27, cleaved caspase-3, cleaved poly (ADP-Ribose) polymerase 1, vascular endothelial growth factor A, tissue inhibitor of metalloproteinases 3 (TIMP3), and trypsin-modified soy protein 10 were assessed by immunoblotting. Cell viability was examined using MTT assays, and the cell cycle and apoptosis were analyzed by flow cytometry. Endothelial cell tube formation capacity was assayed in vitro. GAS5 and p27 levels were found lower in the endometrium samples from patients with endometriosis. Primary ESCs from patients with endometriosis had increased viability, reduced apoptosis, and a relatively uncontrolled cell cycle. Gain- and loss-of-function studies confirmed that GAS5 regulated p27 expression in ESCs. Furthermore, GAS5 level was relatively low in primary endothelial cells from patients with endometriosis and GAS5 acted as an angiogenesis inhibitor by regulating the miR-181c-TIMP3 axis. Thus, lower GAS5 level in endometrium might be related to endometriosis by regulating cell proliferation, apoptosis, cell cycle, and angiogenesis.

Smooth muscle SIRT1 reprograms endothelial cells to suppress angiogenesis after ischemia.

Objective: Vascular smooth muscle cells (VSMCs) undergo the phenotypic changes from contractile to synthetic state during vascular remodeling after ischemia. SIRT1 protects against stress-induced vascular remodeling via maintaining VSMC differentiated phenotype. However, the effect of smooth muscle SIRT1 on the functions of endothelial cells (ECs) has not been well clarified. Here, we explored the role of smooth muscle SIRT1 in endothelial angiogenesis after ischemia and the underlying mechanisms. Methods: We performed a femoral artery ligation model using VSMC specific human SIRT1 transgenic (SIRT1-Tg) and knockout (KO) mice. Angiogenesis was assessed in in vivo by quantification of the total number of capillaries, wound healing and matrigel plug assays, and in vitro ECs by tube formation, proliferation and migration assays. The interaction of HIF1α with circRNA was examined by using RNA immunoprecipitation, RNA pull-down and in situ hybridization assays. Results: The blood flow recovery was significantly attenuated in SIRT1-Tg mice, and markedly improved in SIRT1-Tg mice treated with SIRT1 inhibitor EX527 and in SIRT1-KO mice. The density of capillaries significantly decreased in the ischemic gastrocnemius of SIRT1-Tg mice compared with SIRT1-KO and WT mice, with reduced expression of VEGFA, which resulted in decreased number of arterioles. We identified that the phenotypic switching of SIRT1-Tg VSMCs was attenuated in response to hypoxia, with high levels of contractile proteins and reduced expression of the synthetic markers and NG2, compared with SIRT1-KO and WT VSMCs. Mechanistically, SIRT1-Tg VSMCs inhibited endothelial angiogenic activity induced by hypoxia via the exosome cZFP609. The cZFP609 was delivered into ECs, and detained HIF1α in the cytoplasm via its interaction with HIF1α, thereby inhibiting VEGFA expression and endothelial angiogenic functions. Meantime, the high cZFP609 expression was observed in the plasma of the patients with atherosclerotic or diabetic lower extremity peripheral artery disease, associated with reduced ankle-brachial index. Knockdown of cZFP609 improved blood flow recovery after hindlimb ischemia in SIRT1-Tg mice. Conclusions: Our findings demonstrate that SIRT1 may impair the plasticity of VSMCs. cZFP609 mediates VSMCs to reprogram endothelial functions, and serves as a valuable indicator to assess the prognosis and clinical outcomes of ischemic diseases.

Accumulation of Smooth Muscle 22α Protein Accelerates Senescence of Vascular Smooth Muscle Cells via Stabilization of p53 In Vitro and In Vivo.

OBJECTIVE: Smooth muscle (SM) 22α, an actin-binding protein, displays an upregulated expression as a marker during cellular senescence. However, the causal relationship between SM22α and senescence is poorly understood. This study aimed to investigate the role of SM22α in angiotensin II (Ang II)-induced senescence of vascular smooth muscle cells (VSMCs). APPROACH AND RESULTS: We prepared a model of VSMC senescence induced by Ang II and found that the expression of SM22α in VSMCs was increased in response to chronic Ang II treatment. Overexpression of SM22α promoted Ang II-induced VSMC senescence, whereas knockdown of SM22α suppressed this process. Moreover, this effect of SM22α was p53 dependent. Increased SM22α protein obstructed ubiquitination and degradation of p53 and subsequently improved its stability. Furthermore, SM22α inhibited phosphorylation of Mdm2 (mouse double minute 2 homolog), an E3 ubiquitin-protein ligase, accompanied by a decreased interaction between Mdm2 and p53. Using LY294002, a PI3K/Akt inhibitor, we found that PI3K/Akt-mediated Mdm2 phosphorylation and activation was inhibited in senescent or SM22α-overexpressed VSMCs, in parallel with decreased p53 ubiquitination. We further found that SM22α inhibited activation of PI3K/Akt/Mdm2 pathway via strengthening actin cytoskeleton. In the in vivo study, we showed that the disruption of SM22α reduced the increase of blood pressure induced by Ang II, associated with decreased VSMC senescence through a mechanism similar to that in VSMCs in vitro. CONCLUSIONS: In conclusion, these findings suggest that the accumulation of SM22α promotes Ang II-induced senescence via the suppression of Mdm2-mediated ubiquitination and degradation of p53 in VSMCs in vitro and in vivo.

CKII-SIRT1-SM22α loop evokes a self-limited inflammatory response in vascular smooth muscle cells.

AIMS: Sirtuin 1 (SIRT1) inhibits nuclear factor kappa B (NF-κB) activity in response to the inflammatory cytokine tumour necrosis factor alpha (TNF-α). Smooth muscle (SM) 22α is a phosphorylation-regulated suppressor of IKK-IκBα-NF-κB signalling cascades in vascular smooth muscle cells (VSMCs). Sm22α knockout results in increased expression of pro-inflammatory genes in the aortas which are controlled by NF-κB. This study aimed to investigate the relationship between SM22α and SIRT1 in the control of vascular inflammation. METHODS AND RESULTS: The ligation injury model of Sirt1-Tg/Sm22α-/- mice displayed an increased level of the inflammatory molecules in the carotid arteries compared with Sirt1-Tg mice, accompanied with aggravating neointimal hyperplasia. In the in vitro study, on the one hand, we showed that TNF-α induced the epigenetic silencing of SM22α transcription via EZH2-mediated H3K27 methylation in the SM22α promoter region, contributing to inflammatory response. On the other hand, TNF-α simultaneously induced SIRT1 phosphorylation via CKII and thereby protected against inflammation. Phosphorylated SIRT1 interacted with and deacetylated EZH2 and, subsequently, promoted SM22α transcription by inhibiting EZH2 activity. Increased SM22α in turn facilitated the phosphorylation and activation of SIRT1 via recruitment of CKII to SIRT1, which amplified the anti-inflammatory effect of SIRT1. CONCLUSION: Our findings demonstrate that, in response to TNF-α stimulation, CKII-SIRT1-SM22α acts in a loop to reinforce the expression of SM22α, which limits the inflammatory response in VSMCs in vivo and in vitro. The anti-inflammatory effect of SIRT1 may be dependent on SM22α to some extent. Our data point to targeted activation of SIRT1 in VSMCs as a promising therapeutic avenue in preventing cardiovascular diseases.

Insulin-independent GLUT4 translocation in proliferative vascular smooth muscle cells involves SM22α.

The insulin-sensitive glucose transporter 4 (GLUT4) is a predominant facilitative glucose transporter in vascular smooth muscle cells (VSMCs) and is significantly upregulated in rabbit neointima. This study investigated the role of GLUT4 in VSMC proliferation, the cellular mechanism underlying PDGF-BB-stimulated GLUT4 translocation, and effects of SM22α, an actin-binding protein, on this process. Chronic treatment of VSMCs with PDGF-BB significantly elevated GLUT4 expression and glucose uptake. PDGF-BB-induced VSMC proliferation was dependent on GLUT4-mediated glucose uptake. Meanwhile, the response of GLUT4 to insulin decreased in PDGF-BB-stimulated VSMCs. PDGF-BB-induced GLUT4 translocation partially rescued glucose utilization in insulin-resistant cells. Immunofluorescence and western blot analysis revealed that PDGF-BB induced GLUT4 translocation in an actin dynamics-dependent manner. SM22α disruption facilitated GLUT4 translocation and glucose uptake by promoting actin dynamics and cortical actin polymerization. Similar results were observed in VSMCs of SM22α -/- mice. The in vivo experiments showed that the glucose level in the neointima induced by ligation was significantly increased in SM22α -/- mice, accompanied by increased neointimal thickness, compared with those in wild-type mice. These findings suggest that GLUT4-mediated glucose uptake is involved in VSMC proliferation, and provide a novel link between SM22α and glucose utilization in PDGF-BB-triggered proliferation. KEY MESSAGES: • GLUT4-mediated glucose uptake is required for the VSMC proliferation. • PDGF-BB-induced GLUT4 translocation partially rescues glucose uptake in insulin resistance. • SM22α disruption enhances PDGF-BB-induced GLUT4 translocation. • Glucose level in injured vascular tissue is positively correlated with neointimal hyperplasia.

TRAF6-Mediated SM22α K21 Ubiquitination Promotes G6PD Activation and NADPH Production, Contributing to GSH Homeostasis and VSMC Survival In Vitro and In Vivo.

RATIONALE: Vascular smooth muscle cell (VSMC) survival under stressful conditions is integral to promoting vascular repair, but facilitates plaque stability during the development of atherosclerosis. The cytoskeleton-associated smooth muscle (SM) 22α protein is involved in the regulation of VSMC phenotypes, whereas the pentose phosphate pathway plays an essential role in cell proliferation through the production of dihydronicotinamide adenine dinucleotide phosphate. OBJECTIVE: To identify the relationship between dihydronicotinamide adenine dinucleotide phosphate production and SM22α activity in the development and progression of vascular diseases. METHODS AND RESULTS: We showed that the expression and activity of glucose-6-phosphate dehydrogenase (G6PD) are promoted in platelet-derived growth factor (PDGF)-BB-induced proliferative VSMCs. PDGF-BB induced G6PD membrane translocation and activation in an SM22α K21 ubiquitination-dependent manner. Specifically, the ubiquitinated SM22α interacted with G6PD and mediated G6PD membrane translocation. Furthermore, we found that tumor necrosis factor receptor-associated factor (TRAF) 6 mediated SM22α K21 ubiquitination in a K63-linked manner on PDGF-BB stimulation. Knockdown of TRAF6 decreased the membrane translocation and activity of G6PD, in parallel with reduced SM22α K21 ubiquitination. Elevated levels of activated G6PD consequent to PDGF-BB induction led to increased dihydronicotinamide adenine dinucleotide phosphate generation through stimulation of the pentose phosphate pathway, which enhanced VSMC viability and reduced apoptosis in vivo and in vitro via glutathione homeostasis. CONCLUSIONS: We provide evidence that TRAF6-induced SM22α ubiquitination maintains VSMC survival through increased G6PD activity and dihydronicotinamide adenine dinucleotide phosphate production. The TRAF6-SM22α-G6PD pathway is a novel mechanism underlying the association between glucose metabolism and VSMC survival, which is beneficial for vascular repair after injury but facilitates atherosclerotic plaque stability.

SM22α inhibits vascular inflammation via stabilization of IκBα in vascular smooth muscle cells.

Smooth muscle (SM) 22α, an actin-binding protein, is down-regulated in atherosclerotic arteries. Disruption of SM22α promotes arterial inflammation through activation of reactive oxygen species (ROS)-mediated nuclear factor (NF)-κB pathways. This study aimed to investigate the mechanisms by which SM22α regulates vascular inflammatory response. The ligation injury model of SM22α(-/-) mice displayed up-regulation of inflammatory molecules MCP-1, VCAM-1, and ICAM-1 in the carotid arteries. Similar results were discovered in human atherosclerotic samples. In vitro studies, overexpression of SM22α attenuated TNF-α-induced IκBα phosphorylation and degradation, accompanied by decreased NF-κB activity and reduced inflammatory molecule expression. Using coimmunoprecipitation, we found that SM22α interacted with and stabilized IκBα in quiescent VSMCs. Upon TNF-α stimulation, SM22α was phosphorylated by casein kinase (CK) II at Thr139, leading to dissociation of SM22α from IκBα, followed by IκBα degradation and NF-κB activation. Our findings demonstrate that SM22α is a phosphorylation-regulated suppressor of IKK-IκBα-NF-κB signaling cascades. SM22α may be a novel therapeutic target for human vascular diseases and other inflammatory conditions.

KLF5 and hhLIM cooperatively promote proliferation of vascular smooth muscle cells.

Krüppel-like factor 5 (KLF5) plays an important role in cellular proliferation and differentiation. In this study, we show that adenovirus-mediated overexpression of KLF5 increased neointimal formation, while human heart LIM protein (hhLIM) decreased neointimal formation following vascular injury. Interestingly, neointimal formation was significantly increased in the animals where both hhLIM and KLF5 were introduced, suggesting that KLF5 can reverse hhLIM function in cell proliferation on the coexpression with hhLIM. These results were also confirmed the cellular level. Further mechanistic studies suggested that PDGF-BB promoted the interaction between hhLIM and KLF5 through stimulating hhLIM binding to TGF-ß control element (TCE) on the cyclin E promoter in a KLF5-dependent manner. Failure of KLF5 binding to the TCE, on the knockdown of KLF5 by transfecting siRNA, not only prevented the recruitment of hhLIM to the cyclin E promoter but also affected activation of the cyclin E promoter by KLF5. These data suggest that KLF5 reverses hhLIM function from anti-proliferation to pro-proliferation through its interaction with hhLIM on the cyclin E promoter.

Clinicopathological correlation of Krüppel-like factor 5 and matrix metalloproteinase-9 expression and cartilage degeneration in human osteoarthritis.

The present study was designed to investigate the clinicopathological correlation between the expression of KLF5 and MMP-9, which are associated with extracellular matrix degradation and cartilage degeneration in human knee osteoarthritis (OA). Tibiofemoral joint samples from 20 patients with OA, treated with surgery alone, were divided into two groups: 0=no change (NC, n=17), and severe changes with a higher mean score (≥ 3) (SC, n=29). The latter group contains samples with severe damages in cartilages and subchondral bones at medial tibial plateaux. The expression of the proteins was detected by immunofluorescence and quantitative RT-PCR, respectively. Neurovascular invasion was evaluated by protein gene product (PGP) 9.5 and CD34-positive staining and scanning electron microscopy, respectively. Safranin O staining showed that the sections from the SC group had increased cartilage degeneration. The number of vascular invasions in the SC group (16/29, 55.2%) was higher than that in NC controls (2/17, 11.7%, P<0.05). The expression of KLF5 and MMP-9 increased, and was co-localized in the same cells of SC cartilages. The severity of cartilage degeneration and vascular invasion was associated with upregulation of the two protein expressions and was significantly different between SC and NC samples (P<0.05). Taken together, the expression of KLF5 and MMP-9 may be involved in cartilage degeneration, contributing to human OA.

Flavonoids from Inula britannica reduces oxidative stress through inhibiting expression and phosphorylation of p47(phox) in VSMCs.

CONTEXT: Inula britanica Linn. (Compositae) is a traditional Chinese medicinal herb that has been used to treat bronchitis and inflammation. The total flavonoid extracts (TFEs) isolated from its flowers can inhibit neointimal formation induced by balloon injury in vivo. OBJECTIVE: To investigate the mechanism by which TFE suppresses oxidative stress generation and the subsequent inflammation response in vitro. MATERIALS AND METHODS: The cultured vascular smooth muscle cells (VSMCs) form rats were exposed to oxidative stress following pretreatment with or without TFE at different concentration. Then, fluorescence staining was used to detect superoxide anion (O2(˙-)) production, and the lever of maleic dialdehyde (MDA) and superoxide dismutase (SOD) was measured at the same time. Furthermore, tumor necrosis factor-α (TNF-α) was measured by enzyme linked immunosorbent assay (ELISA), reverse transcription-PCR and western blot were performed to detect the expression activity of p47(phox) gene, and immunoprecipitation was used to test the level of p47(phox) phosphorylation. RESULTS: TFE inhibited the production of O2(˙-) induced by H2O2 in VSMCs, with decrease in secretion of TNF-α; elevated the activity of SOD in the medium, similar to the effect of quercetin; reduced the level of MDA in culture medium of VSMCs. The pretreatment with TFE resulted in decrease the level of p47(phox) mRNA and protein, and even p47(phox) phosphorylation in VSMCs, compared with H2O2 control. DISCUSSION AND CONCLUSION: These findings demonstrate that TFE is capable of attenuating the oxidative stress generation and the subsequent inflammation response via preventing the overexpression and activation of p47(phox) and the increased TNF-α secretion in VSMCs in vitro.

Baicalin inhibits PDGF-BB-stimulated vascular smooth muscle cell proliferation through suppressing PDGFRß-ERK signaling and increase in p27 accumulation and prevents injury-induced neointimal hyperplasia.

The increased proliferation and migration of vascular smooth muscle cells (VSMCs) are key events in the development of atherosclerotic lesions. Baicalin, an herb-derived flavonoid compound, has been previously shown to induce apoptosis and growth inhibition in cancer cells through multiple pathways. However, the potential role of baicalin in regulation of VSMC proliferation and prevention of cardiovascular diseases remains unexplored. In this study, we show that pretreatment with baicalin has a dose-dependent inhibitory effect on PDGF-BB-stimulated VSMC proliferation, accompanied with the reduction of proliferating cell nuclear antigen (PCNA) expression. We also show that baicalin-induced growth inhibition is associated with a decrease in cyclin E-CDK2 activation and increase in p27 level in PDGF-stimulated VSMCs, which appears to be at least partly mediated by blockade of PDGF receptor ß (PDGFRß)-extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. In addition, baicalin was also found to inhibit adhesion molecule expression and cell migration induced by PDGF-BB in VSMCs. Furthermore, using an animal carotid arterial balloon-injury model, we found that baicalin significantly inhibited neointimal hyperplasia. Taken together, our results reveal a novel function of baicalin in inducing growth arrest of PDGF-stimulated VSMCs and suppressing neointimal hyperplasia after balloon injury, and suggest that the underlying mechanism involves the inhibition of cyclin E-CDK2 activation and the increase in p27 accumulation via blockade of the PDGFRß-ERK1/2 signaling cascade.

Blockade of the Ras-extracellular signal-regulated kinase 1/2 pathway is involved in smooth muscle 22 alpha-mediated suppression of vascular smooth muscle cell proliferation and neointima hyperplasia.

OBJECTIVE: Vascular smooth muscle cells (VSMCs) can switch between differentiated and dedifferentiated phenotypes, and this phenotype switch is believed to be essential for repair of vascular injury. We studied the inhibitory effect of smooth muscle 22 alpha (SM22 alpha) on VSMC proliferation in vitro and in vivo and explored the potential molecular mechanisms of this effect. METHODS AND RESULTS: By using coimmunoprecipitation and glutathione S-transferase pull-down assays, we have shown that SM22 alpha binds to Ras in SM22 alpha-overexpressed VSMCs in the presence or absence of platelet-derived growth factor-BB stimulation. SM22 alpha arrested cell cycle progression through segregation of Ras with Raf-1 and downregulation of the Raf-1-MEK1/2-extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signaling cascade. The inhibitory effect of SM22 alpha on VSMC proliferation was verified in vivo. The infection of rat carotid arteries with recombinant adenovirus encoding SM22 alpha inhibited neointimal hyperplasia via suppression of the Raf-1-MEK1/2-extracellular signal-regulated kinase 1/2 signaling pathway. CONCLUSIONS: These findings suggest that high expression of SM22 alpha inhibits cell proliferation via reduction of the response to mitogen stimuli in VSMCs and provide a novel mechanism by which VSMCs maintain their contractile phenotype and resist mitogenic stimuli in an SM22 alpha-dependent manner.

Polymorphisms of the ICAM-1 exon 6 (E469K) are associated with differentiation of colorectal cancer.

BACKGROUND: Genetic factors are thought to play a role in development for colorectal carcinogenesis. ICAM-1 is a polymorphic gene, thus, the present study investigated the relationship between the polymorphisms of ICAM-1 and the susceptibility and phenotypical characteristics of colorectal cancer (CRC). METHODS: The polymorphisms at ICAM-1 exon 4 (G241R) and exon 6 (E469K) were detected by PCR with sequence-specific primers. The relationship between specific genotypes of ICAM-1 and differentiation of CRC was evaluated by the histological grade. RESULTS: We showed only GG genotype of ICAM-1 individuals in either CRC or normal controls. The KK genotype of ICAM-1 K469E was found more frequently than in the controls (P < 0.05). Patients with well-differentiated CRC displayed the KK more frequently than those of poor differentiation (P < 0.05). CONCLUSION: The findings indicate that polymorphisms of G241R are rare in Chinese population and that KK genotype of ICAM-1 K469E is significantly associated with well differentiation of CRC.

Synthetic retinoid Am80 inhibits interaction of KLF5 with RAR alpha through inducing KLF5 dephosphorylation mediated by the PI3K/Akt signaling in vascular smooth muscle cells.

Krüppel-like factor 5 (KLF5) is known to physically interact with retinoic acid receptor-alpha (RAR alpha). Here, we show that Am80 inhibited the interaction between KLF5 and RAR alpha and this inhibitory effect was accompanied by the dephosphorylation of KLF5 in VSMCs. Treating VSMCs with LY294002, the PI3K/Akt inhibitor, abrogated Am80-induced KLF5 dephosphorylation and reversed Am80-induced suppression of interaction between KLF5 and RAR alpha, whereas treating vascular smooth muscle cells (VSMCs) with SB203580, the p38 kinase inhibitor, attenuated the interaction between KLF5 and RAR alpha. Constitutively active p38 kinase MKK6b infection prevented the KLF5 dephosphorylation induced by Am80. In conclusion, Am80 induces KLF5 dephosphorylation by activating PI3K/Akt signaling, and inhibits KLF5 phosphorylation by blocking p38 signaling, subsequently leading to the suppression of interaction of KLF5 with RAR alpha.