interacts_with DB00784?
Specific Biomarkers Are Associated with Docetaxeland Gemcitabine-Resistant NSCLC Cell Lines . Five-year survival rate for lung cancer is limited to 10 % to 15 % . Therefore , the identification of novel therapeutic prognostic factors is an urgent requirement . The aim of this study is thus to highlight specific biomarkers in chemoresistant non-small cell lung cancer cell lines . Therefore , we checked-in the control condition as well as after short-term pharmacological treatment with either docetaxel or gemcitabine-the expression of genes such as tumor suppressor genes ( CDKN2A , P53355 , P49789 , P09211 , P16455 , RARβ2 , RASSF1A , and P35625 ) , genes associated with drug resistance ( P38398 , P35354 , P07992 , P17936 , P23921 , and Q13509 ) , and stemness-related genes ( CD133 , Q01860 , and O43623 ) in two cellular models of squamous carcinoma ( CAEP ) and adenocarcinoma ( RAL ) of the lung originally established . Their promoter methylation profile was also evaluated . Drug-related genes were upregulated . DB00515 resistance matched with high levels of P38398 and P07992 in both cell lines ; docetaxel sensitivity of CAEP cells was associated to levels of Q13509 lower than RAL cells . Although CAEP cells were more sensitive to gemcitabine , both cell lines showed high levels of P23921 . Stemness-related genes were downregulated in the control condition but became upregulated in docetaxel-resistant cells , indicating the selection of a population with stemness features . We did not find an unequivocal correspondence between gene expression and respective DNA promoter methylation status , suggesting the involvement of additional mechanisms of gene expression regulation . These results highlight specific biomarkers consistent with the different responses of the two cell lines to standard pharmacological treatments and indicate specific molecular traits for their chemoresistance . Immunomodulatory drugs inhibit expression of cyclooxygenase-2 from P01375 , IL-1beta , and LPS-stimulated human PBMC in a partially P22301 -dependent manner . Immunomodulatory drugs ( IMiDs ) are potent inhibitors of P01375 and IL-1beta and elevators of P22301 production in LPS-stimulated human PBMC . They are currently in clinical trials for various diseases , including multiple myeloma , myelodysplastic syndrome , and melanoma . In the present study , we have investigated the effects of thalidomide , DB00480 and CC-4047 on the expression of P35354 by stimulated PBMC . Our results show that thalidomide and IMiDs inhibited the expression of P35354 but not the P23219 protein in LPS- P01375 and IL-1beta stimulated PBMC and shortened the half-life of P35354 mRNA in a dose-dependent manner . They also inhibited the synthesis of prostaglandin E2 from LPS-stimulated PBMC . While anti- P01375 or IL-1beta neutralizing antibodies had no effect on P35354 expression , anti- P22301 neutralizing antibody elevated the expression of P35354 mRNA , and protein from treated PBMC . These data suggest that the anti-inflammatory and anti-tumor effects of IMiDs may be due in part to elevation of P22301 production and its subsequent inhibition of P35354 expression . P16070 -mediated cyclooxygenase-2 expression and thromboxane A2 production in RAW 264.7 macrophages . OBJECTIVE AND DESIGN : P16070 is the major cell surface receptor for hyaluronan ( HA ) on macrophages . Stimulation of macrophages via the HA- P16070 pathway leads to the enhanced expression of inflammatory gene products , including cytokines , chemokines , and adhesion molecules . We have examined whether activation of P16070 by crosslinking is capable of activating the cyclooxygenase ( P36551 ) and prostaglandin ( PG ) /thromboxane ( TX ) pathway in cultured macrophages . MATERIALS AND METHODS : P16070 was crosslinked on RAW 264.7 mouse macrophages using specific rat anti-mouse P16070 monoclonal antibodies and anti-rat IgG . Total RNA was extracted and subjected to RT-PCR analysis for genes of the PG/TX synthetic pathway . Supernatants were analyzed for DB00917 and TXB2 using specific ELISAs . RESULTS : Transcripts for P23219 , P35354 , TX synthase ( P24557 ) , and DB00917 synthase ( O14684 ) were all constitutively expressed in the mouse macrophage cell line RAW 264.7 . Crosslinking of P16070 markedly enhanced P35354 and weakly increased P24557 mRNA , whereas P23219 and O14684 mRNA did not change significantly in these cells . Crosslinking of P16070 selectively increased the production of TXB2 but not DB00917 . CONCLUSIONS : These findings suggest that the activation of the P16070 pathway plays a unique role in PG synthesis . Activation of this pathway results in enhanced TXA2 but not DB00917 production . This leads to an imbalance of the TXA2/ DB00917 profile which favors a proinflammatory and vasoconstrictory response . Cellular distribution and contribution of cyclooxygenase P35354 to diabetogenesis in NOD mouse . Unlike most other mammalian cells , beta-cells of Langerhans constitutively express cyclooxygenase ( P36551 ) -2 rather than P23219 . P35354 is also constitutively expressed in type 1 diabetes ( T1D ) patients ' periphery blood monocytes and macrophage . To understand the role of P35354 in the beta-cell , we investigated P35354 expression in beta-cells and islet infiltrates of NOD and BALB/c mice using fluorescence immunohistochemistry and cytochemical confocal microscopy and Western blotting . Immunostaining showed that P35354 is expressed in islet-infiltrating macrophages , and that the expression of insulin and P35354 disappeared concomitantly from the beta-cells when NOD mice progressed toward overt diabetes . Also cultured P01308 -1E cells coexpressed insulin and P35354 but clearly in different subcellular compartments . Treatment with celecoxib increased insulin release from these cells in a dose-dependent manner in glucose concentrations ranging from 5 to 17 mM . Excessive P35354 expression by the islet-infiltrating macrophages may contribute to the beta-cell death during insulitis . The effects of celecoxib on P01308 -1E cells suggest that PGE(2) and other downstream products of P35354 may contribute to the regulation of insulin release from the beta-cells . Cytokine responses of intestinal epithelial-like Caco-2 cells to non-pathogenic and opportunistic pathogenic yeasts in the presence of butyric acid . Candida albicans , Saccharomyces cerevisiae and their cell wall components , zymosan and glucan , have been shown to stimulate interleukin-8 ( P10145 /CXCL-8 ) production by intestinal epithelial cell-like Caco-2 cells pre-cultured with 10 mM butyric acid . We examined in this study whether these yeasts also altered the production of other cytokines and cyclooxygenases ( COXs ) by Caco-2 cells . Culturing Caco-2 cells with 10 mM butyric acid and 15 % FBS for 4 days enhanced the basal levels of mRNA encoding P05231 , P10145 , Q14116 , monocyte chemoattractant protein ( MCP ) -1 , stem cell factor , transforming growth factor ( TGF ) -beta1 , TGF-beta3 , tumor necrosis factor ( P01375 ) -alpha , P23219 , and P35354 , but not of granulocyte-macrophage colony-stimulating factor ( GM- P04141 ) and TGF-beta2 . The inclusion of live S. cerevisiae or C. albicans further enhanced the production of P10145 , but not of the other cytokines and COXs . The non-pathogenic yeasts , C. kefyr , C. utilis , C. versatilis , Kluyveromyces lactis , K. marxianus , Schizosaccharomyces pombe and Zygosaccharomyces rouxii , used for the production of fermented foods and probiotics , and the opportunistic pathogens , C. glabrata , C. krusei , C. parapsilosis and C. tropicalis , isolated from human tissue samples also enhanced P10145 secretion by Caco-2 cells . Expression of the human concentrative nucleotide transporter 1 ( O00337 ) gene correlates with clinical response in patients affected by Waldenström 's Macroglobulinemia ( WM ) and small lymphocytic lymphoma ( SLL ) undergoing a combination treatment with 2-chloro-2'-deoxyadenosine ( DB00242 ) and DB00073 . PURPOSE : Resistance to nucleoside analogues agents is likely to be multifactorial and could involve a number of mechanisms affecting drug penetration , metabolism and targeting . In vitro studies of resistant human cell lines have confirmed that human concentrative nucleoside transporter 1 ( O00337 ) -deficient cells display resistance . EXPERIMENTAL DESIGN : We applied real-time PCR method to assess the mRNA expression of equilibrative and concentrative nucleoside transporter ( hENT1 , O00337 ) , deoxycytidine and deoxyguanosine kinase ( P27707 , Q16854 ) , 5'-nucleotidase ( 5'-NT ) , ribonucleotide reductase catalytic and regulatory ( P23921 , P31350 ) subunits in bone marrow cells from 32 patients with Waldenström 's Macroglobulinemia ( WM ) and small lymphocytic lymphoma ( SLL ) who received 2CdA-based chemotherapy . Responses to chemotherapy , were then correlated to the expression of these markers . RESULTS : All 32 patients enrolled expressed lower levels of O00337 as compared to healthy donors . In univariate analysis , lower expression level of O00337 ( p=0.0021 ) and P31350 ( p=0.02 ) correlated with response to chemotherapy . In particular , patients with low levels of O00337 achieved inferior clinical response . No significant correlation between these genes expression and age , stage of disease was found . This study suggests that nucleotidase expression levels can be used to identify subgroups of WM and SLL patients who will likely respond differently to a 2CdA-based therapy . DB00533 produces intestinal but not gastric damage in the presence of a low dose of indomethacin in rats . Indomethacin in small doses is known to inhibit prostaglandin ( PG ) production , yet it does not damage the gastrointestinal mucosa . We examined whether a cyclooxygenase ( P36551 ) -2 inhibitor induces gastrointestinal damage in the presence of a low dose of indomethacin and investigated the ulcerogenic mechanism in relation to P35354 expression . Rats with or without 18-h fasting were administered rofecoxib ( a selective P35354 inhibitor ; 10 or 30 mg/kg p.o. ) in the absence or presence of indomethacin ( 3 mg/kg p.o. ) , and the gastric or intestinal mucosa was examined 8 and 24 h later , respectively . Neither indomethacin nor rofecoxib alone caused damage in the stomach or small intestine . However , indomethacin damaged the small intestine in the presence of rofecoxib , yet the same treatment did not damage the stomach . Indomethacin reduced the mucosal DB00917 content in both tissues , whereas rofecoxib did not . The P35354 mRNA was up-regulated in the intestine but not the stomach after indomethacin treatment , and the reduced DB00917 content was significantly recovered later only in the small intestine , in a rofecoxib-inhibitable manner . Indomethacin produced hypermotility in the small intestine but not the stomach , whereas rofecoxib had no effect . These results suggest that the PG deficiency caused by a low dose of indomethacin produces hypermotility and P35354 expression in the small intestine but not the stomach , resulting in damage when P35354 is inhibited . It is assumed that the hypermotility response is a key event in the expression of P35354 and thereby important in the development of mucosal damage in the gastrointestinal tract . Investigation of the binding of isoform-selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform-selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time-resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped-flow kinetic studies reveal that the rate of quenching is limited by a first-order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange . Q96P20 /cryopyrin is necessary for interleukin-1beta ( IL-1beta ) release in response to hyaluronan , an endogenous trigger of inflammation in response to injury . Inflammation under sterile conditions is a key event in autoimmunity and following trauma . DB08818 , a glycosaminoglycan released from the extracellular matrix after injury , acts as an endogenous signal of trauma and can trigger chemokine release in injured tissue . Here , we investigated whether Q96P20 /cryopyrin , a component of the inflammasome , participates in the inflammatory response to injury or the cytokine response to hyaluronan . Mice with a targeted deletion in cryopyrin showed a normal increase in Cxcl2 in response to sterile injuries but had decreased inflammation and release of interleukin-1beta ( IL-1beta ) . Similarly , the addition of hyaluronan to macrophages derived from cryopyrin-deficient mice increased release of Cxcl2 but did not increase IL-1beta release . To define the mechanism of hyaluronan-mediated activation of cryopyrin , elements of the hyaluronan recognition process were studied in detail . IL-1beta release was inhibited in peritoneal macrophages derived from P16070 -deficient mice , in an MH-S macrophage cell line treated with antibodies to P16070 , or by inhibitors of lysosome function . The requirement for P16070 binding and hyaluronan internalization could be bypassed by intracellular administration of hyaluronan oligosaccharides ( 10-18-mer ) in lipopolysaccharide-primed macrophages . Therefore , the action of P16070 and subsequent hyaluronan catabolism trigger the intracellular cryopyrin --> IL-1beta pathway . These findings support the hypothesis that hyaluronan works through IL-1beta and the cryopyrin system to signal sterile inflammation . P62937 is required for efficient human cytomegalovirus DNA replication and reactivation . Human cytomegalovirus ( HCMV ) is a large DNA virus belonging to the subfamily Betaherpesvirinae . Haematopoietic cells of the myeloid lineage have been shown to harbour latent HCMV . However , following terminal differentiation of these cells , virus is reactivated , and in an immunocompromised host acute infection can occur . It is currently unknown which viral and cellular factors are involved in regulating the switch between lytic and latent infections . P62937 ( CyPA ) is a cellular protein that acts as a major factor in virus replication and/or virion maturation for a number of different viruses , including human immunodeficiency virus , hepatitis C virus , murine cytomegalovirus , influenza A virus and vaccinia virus . This study investigated the role of CyPA during HCMV infection . CyPA expression was silenced in human foreskin fibroblast ( HF ) and THP-1 cells using small interfering RNA ( siRNA ) technology , or the cells were treated with cyclosporin A ( DB00091 ) to inhibit CyPA activity . Silencing CyPA in HF cells with siRNA resulted in an overall reduction in virus production characterized by delayed expression of immediate-early ( IE ) proteins , decreased viral DNA loads and reduced titres . Furthermore , silencing of CyPA in THP-1 cells pre- and post-differentiation prevented IE protein expression and virus reactivation from a non-productive state . Interestingly , it was observed that treatment of THP-1 cells with DB00091 prevented the cells from establishing a fully latent infection . In summary , these results demonstrate that CyPA expression is an important factor in HCMV IE protein expression and virus production in lytically infected HF cells , and is a major component in virus reactivation from infected THP-1 cells . Anti-inflammatory effect of transduced PEP-1-cyclophilin A in Raw264.7 cells and 12-O-tetradecanoylphorbol-13-acetate-induced mice . AIMS : P62937 ( CypA ) is an immunophilin that acts as a receptor for the immunosuppressant drug cyclosporine A ( DB00091 ) . CypA has emerged as a potential drug target for several inflammatory diseases , although the details of its mechanism are unclear . We examined the protective effects of CypA on inflammation in Raw 264.7 cells and animal models . MAIN METHODS : A human CypA gene was fused with a protein transduction domain , PEP-1 peptide , to construct a cell permeable PEP-1-CypA protein . The protein expression level of cyclooxygenase-2 ( P35354 ) and cytokines was detected by Western blot , ELISA and mRNA level of P35354 and cytokines were measured by RT-PCR . The nuclear factor-kappa B ( NF-kB ) and mitogen-activated protein kinase ( MAPK ) activation were analyzed by Western blot and electrophoretic mobility shift assay . Skin inflammation was detected with immunohistochemistry . KEY FINDINGS : Transduced PEP-1-CypA protein markedly inhibited lipopolysaccharide- and 12-O-tetradecanoyl phorbol-13-acetate-induced expression levels of P35354 as well as pro-inflammatory cytokine levels in vitro and in vivo . Furthermore , transduced PEP-1-CypA protein resulted in a significant reduction in the activation of NF-kB and MAPK . SIGNIFICANCE : The results indicate that PEP-1-CypA inhibits inflammatory response cytokines and enzymes by blocking NF-kB and MAPK activation upon stimulation of inflammation in vitro and in vivo . PEP-1-CypA protein may potentially be used as a therapeutic agent against skin diseases-related inflammation . DB00114 values in cerebrospinal fluid : reference values and diagnosis of Q9NVS9 deficiency in paediatric patients . Our aim was to establish reference values for cerebrospinal fluid ( P04141 ) pyridoxal 5'-phosphate ( PLP ) in a paediatric population for the diagnosis of pyridox(am)ine 5'-phosphate oxidase ( Q9NVS9 ) deficiency . For reference values , P04141 samples from 113 paediatric controls ( age range : 1 day-18 years ) from Barcelona and London were analysed . Cerebrospinal fluid PLP and biogenic amine concentrations were analysed by HPLC with fluorescence and electrochemical detection . DB00114 concentrations in 4 patients with Q9NVS9 deficiency were determined . A negative correlation between P04141 PLP values and age of controls was observed in both populations ( r=-0.503 ; p < 0.0001 and r=-0.542 ; p=0.002 ) . Reference values were stratified into 4 ( Barcelona ) and 3 age groups ( London ) . For the newborn period , P04141 PLP reference intervals were 32-78 and 44-89 nmol/L for the Barcelona and London centers , respectively ) . No correlation was observed in the different age groups between PLP values and biogenic amines metabolites . PLP values in neonates with Q9NVS9 deficiency were clearly decreased ( PLP=3.6 , 12.0 , 14.0 and 18.0 nmol/L ) compared with our reference ranges . In conclusion , reference values for P04141 PLP should be stratified according to age . No association was observed between PLP values and biogenic amines metabolites . In our 4 cases with Q9NVS9 deficiency , P04141 PLP values were clearly below the reference values . Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . DB00784 ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose-dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy . Targeting the PI3K/ P42345 axis , alone and in combination with autophagy blockade , for the treatment of malignant peripheral nerve sheath tumors . There is a critical need for efficacious therapeutic strategies to improve the outcome of patients afflicted by malignant peripheral nerve sheath tumors ( MPNST ) . Multiple lines of evidence suggest a role for deregulated phosphoinositide 3-kinase ( PI3K ) / P42345 signaling in MPNST , making this axis an attractive target for therapeutic manipulation . On the basis of previous observations obtained from in vitro experimentation , here we aimed to assess the effects of PI3K/ P42345 blockade on MPNST growth in vivo . The anti-MPNST impact of DB05241 , a dual PI3K/ P42345 inhibitor currently being evaluated in human cancer clinical trials , was tested in two human MPNST xenograft models ( STS26T and MPNST724 ) and an experimental model of pulmonary metastasis ( STS26T ) . DB05241 abrogated human MPNST local and metastatic growth in severe combined immunodeficient mice . Notably , this therapeutic approach failed to induce apoptosis in MPNST cells but rather resulted in marked productive autophagy . Importantly , genetic and pharmacologic autophagy blockade reversed apoptotic resistance and resulted in significant PI3K/ P42345 inhibition-induced MPNST cell death . The addition of the autophagy inhibitor , chloroquine , to the therapeutic regimen of MPNST xenografts after pretreatment with DB05241 resulted in superior antitumor effects as compared with either agent alone . Together , preclinical studies described here expand our previous findings and suggest that PI3K/ P42345 inhibition alone and ( most importantly ) in combination with autophagy blockade may comprise a novel and efficacious therapy for patients harboring MPNST . The Medicinal Timber Canarium patentinervium Miq . ( Burseraceae Kunth. ) Is an Anti-Inflammatory Bioresource of Dual Inhibitors of Cyclooxygenase ( P36551 ) and 5-Lipoxygenase ( 5- P28300 ) . The barks and leaves extracts of Canarium patentinervium Miq . ( Burseraceae Kunth. ) were investigated for cyclooxygenase ( P36551 ) and P09917 ( P28300 ) inhibition via in vitro models . The corresponding antioxidative power of the plant extract was also tested via nonenzyme and enzyme in vitro assays . The ethanolic extract of leaves inhibited the enzymatic activity of 5- P28300 , P23219 , and P35354 with IC50 equal to 49.66 ± 0.02 μg/mL , 0.60 ± 0.01 μg/mL , and 1.07 ± 0.01 μg/mL , respectively , with selective P35354 activity noted in ethanolic extract of barks with P23219 / P35354 ratio of 1.22 . The ethanol extract of barks confronted oxidation in the ABTS , DPPH , and P42345 assay with EC50 values equal to 0.93 ± 0.01 μg/mL , 2.33 ± 0.02 μg/mL , and 67.00 ± 0.32 μg/mL , respectively , while the ethanol extract of leaves confronted oxidation in β-carotene bleaching assay and superoxide dismutase ( SOD ) assay with EC50 value of 6.04 ± 0.02 μg/mL and IC50 value of 3.05 ± 0.01 μg/mL . The ethanol extract acts as a dual inhibitor of P28300 and P36551 enzymes with potent antioxidant capacity . The clinical significance of these data is quite clear that they support a role for Canarium patentinervium Miq . ( Burseraceae Kunth. ) as a source of lead compounds in the management of inflammatory diseases . DB00428 diabetes and the expression of P11166 at the brush border and basolateral membranes of intestinal enterocytes . Changes in membrane expression of sodium-dependent glucose transporter ( P13866 ) and glucose transporter isoform ( P11168 ) protein have been implicated in the increased intestinal glucose transport in streptozotocin-diabetes . The possible involvement of P11166 in the transport response , however , has not previously been studied . Using confocal microscopy on tissue sections and Western blotting of purified brush border membrane ( BBM ) and basolateral membrane ( BLM ) , we have examined enterocyte expression of P11166 in untreated and in 1 and 21 day streptozotocin diabetic rats . In control enterocytes , P11166 was absent at the BBM and detected at low levels at the BLM . Diabetes resulted in a 4- to 5-fold increased expression of P11166 at the BLM and the protein could also be readily detected at the BBM . P01308 treatment of diabetic rats increased P11166 level at the BBM but was without effect on expression of the protein at the BLM . DB02426 effects on brown-fat mitochondria imply that the adenine nucleotide translocator isoforms P12235 and P05141 may be responsible for basal and fatty-acid-induced uncoupling respectively . In brown-fat mitochondria , fatty acids induce thermogenic uncoupling through activation of P25874 ( uncoupling protein 1 ) . However , even in brown-fat mitochondria from P25874 -/- mice , fatty-acid-induced uncoupling exists . In the present investigation , we used the inhibitor CAtr ( carboxyatractyloside ) to examine the involvement of the ANT ( adenine nucleotide translocator ) in the mediation of this P25874 -independent fatty-acid-induced uncoupling in brown-fat mitochondria . We found that the contribution of ANT to fatty-acid-induced uncoupling in P25874 -/- brown-fat mitochondria was minimal ( whereas it was responsible for nearly half the fatty-acid-induced uncoupling in liver mitochondria ) . As compared with liver mitochondria , brown-fat mitochondria exhibit a relatively high ( P25874 -independent ) basal respiration ( ' proton leak ' ) . Unexpectedly , a large fraction of this high basal respiration was sensitive to CAtr , whereas in liver mitochondria , basal respiration was CAtr-insensitive . Total ANT protein levels were similar in brown-fat mitochondria from wild-type mice and in liver mitochondria , but the level was increased in brown-fat mitochondria from P25874 -/- mice . However , in liver , only Ant2 mRNA was found , whereas in brown adipose tissue , Ant1 and Ant2 mRNA levels were equal . The data are therefore compatible with a tentative model in which the P05141 isoform mediates fatty-acid-induced uncoupling , whereas the P12235 isoform may mediate a significant part of the high basal proton leak in brown-fat mitochondria . p62 links β-adrenergic input to mitochondrial function and thermogenesis . The scaffold protein p62 ( sequestosome 1 ; Q13501 ) is an emerging key molecular link among the metabolic , immune , and proliferative processes of the cell . Here , we report that adipocyte-specific , but not CNS- , liver- , muscle- , or myeloid-specific p62-deficient mice are obese and exhibit a decreased metabolic rate caused by impaired nonshivering thermogenesis . Our results show that p62 regulates energy metabolism via control of mitochondrial function in brown adipose tissue ( Q14032 ) . Accordingly , adipocyte-specific p62 deficiency led to impaired mitochondrial function , causing Q14032 to become unresponsive to β-adrenergic stimuli . Ablation of p62 leads to decreased activation of p38 targets , affecting signaling molecules that control mitochondrial function , such as P15336 , CREB , PGC1α , Q92813 , NRF1 , CYTC , P35354 , ATP5β , and P25874 . p62 ablation in HIB1B and Q14032 primary cells demonstrated that p62 controls thermogenesis in a cell-autonomous manner , independently of brown adipocyte development or differentiation . Together , our data identify p62 as a novel regulator of mitochondrial function and brown fat thermogenesis .