The central regulator of adipogenesis, PPARc, is a nuclear receptor that is linked to obesity and metabolic diseases. Here we report that MKRN1 is an E3 ligase of PPARc that induces its ubiquitination, followed by proteasome-dependent degradation. Furthermore, we identified two lysine sites at 184 and 185 that appear to be targeted for ubiquitination by MKRN1. Stable overexpression of MKRN1 reduced PPARc protein levels and suppressed adipocyte differentiation in 3T3-L1 and C3H10T1/2 cells. In contrast, MKRN1 depletion stimulated adipocyte differentiation in these cells. Finally, MKRN1 knockout MEFs showed an increased capacity for adipocyte differentiation compared with wild-type MEFs, with a concomitant increase of PPARc and adipogenic markers. Together, these data indicate that MKRN1 is an elusive PPARc E3 ligase that targets PPARc for proteasomal degradation by ubiquitin-dependent pathways, and further depict MKRN1 as a novel target for diseases involving PPARc. Cell Death and Differentiation (2014) 21, 594-603; doi:10.1038/cdd.2013.181; published online 13 December 2013Excessive body fat in obese individuals is considered a major cause of insulin resistance, cardiovascular diseases, and diabetes.1 In obesity, adipocytes alter the status of energy homeostasis by the generation of adipokines, demonstrating that adipocytes have active roles in energy homeostasis and body composition, in addition to storage of triglycerides.

SD-OCT PPAA detects localized RNFLDs with high sensitivity and specificity, which are comparable to the cpRNFL thickness profile of OCT. These findings suggest that the PPAA can be complementary to other tests for diagnosing glaucoma in patients with localized RNFLDs.

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Given their crucial role in apoptosis suppression, inhibitor of apoptosis proteins (IAPs) have recently become attractive targets for cancer therapy. Here, we report that cellular IAP2 (cIAP2) is specifically stabilized in several cancer cell lines, leading to resistance to Smac mimetics, such as BV6 and birinapant. In particular, our results showed that cIAP2 depletion, but not cIAP1 depletion, sensitized cancer cells to Smac mimetic-induced apoptosis. Ubiquitin-specific protease 11 (USP11) is a deubiquitylase that directly stabilizes cIAP2. USP11 overexpression is frequently found in colorectal cancer and melanoma and is correlated with poor survival. In our study, cancer cell lines expressing high levels of USP11 exhibited strong resistance to Smac mimetic-induced cIAP2 degradation. Furthermore, USP11 downregulation sensitized these cells to apoptosis induced by TRAIL and BV6 and suppressed tumor growth in a xenograft model. Finally, the TNFα/JNK pathway induced USP11 expression and maintained cIAP2 stability, suggesting an alternative TNFα-dependent cell survival pathway. Collectively, our data suggest that USP11-stabilized cIAP2 may serve as a barrier against IAP-targeted clinical approaches.

Localized RNFL defect was closer to the center of the macula in group A than in group B, whereas width of defects was not different between the 2 groups. These findings provide indirect evidence to suggest that more than one pathogenic mechanism may exist in the development of RNFL defects in NTG.

The molecular mechanisms controlling post-translational modifications of p21 have been pursued assiduously in recent years. Here, utilizing mass-spectrometry analysis and site-specific acetyl-p21 antibody, two lysine residues of p21, located at aminoacid sites 161 and 163, were identified as Tip60-mediated acetylation targets for the first time. Detection of adriamycin-induced p21 acetylation, which disappeared after Tip60 depletion with concomitant destabilization of p21 and disruption of G1 arrest, suggested that Tip60-mediated p21 acetylation is necessary for DNA damage-induced cell-cycle regulation. The ability of 2KQ, a mimetic of acetylated p21, to induce cell-cycle arrest and senescence was significantly enhanced in p21 null MEFs compared with those of cells expressing wild-type p21. Together, these observations demonstrate that Tip60-mediated p21 acetylation is a novel and essential regulatory process required for p21-dependent DNA damage-induced cell-cycle arrest. A plethora of cellular perturbations stimulate cells to halt their growth progression by activating numerous cell-cycle inhibitors and apoptotic factors. Among these, p21 is a key member whose major function is to suppress the activities of cyclindependent kinases (CDKs).1,2 This, in turn, leads to cellular growth arrest at a certain stage of the cell cycle mainly as a result of the inhibition of RB or cyclin B phosphorylation. 2-4The induction of p21 requires the presence of p53, a potent tumor suppressor, as its major transcriptional regulator. 5,6 In addition to transcriptional regulation, a variety of regulatory proteins that modulate the activity of p21 in its posttranslational stage have been characterized. 7-13 For example, several E3 ligases, including CUL1, CUL4, and APC2 complexes, function to constitutively induce destabilization of p21 and facilitate cell-cycle progress.9 In addition to these ligases, p21 levels are closely monitored under normal cellular conditions by other E3 ligases, such as MKRN1, p53RFP, and RNF126, in order to facilitate senescent-free progression. 11,13,14 The interaction of histone deacetylases (HDACs) with p21 was also identified in a recent study, suggesting a possible acetylation process for p21. 15Tip60, originally identified as HIV-1 interacting acetyltransferase, is a member of the MYST family, which contains MOZ, Ybf2/Sas2, and Sas2 motifs. 16,17 Tip60-mediated acetylation of H2AX, a member of the histone family of proteins that plays a major role in DNA repair, helps to enhance DNA dynamics upon DNA-damaging stresses. 18,19 On the other hand, nonhistone proteins targeted by Tip60 include ATM, p53, and Myc, among others. 20,21 Tip60 can mediate the acetylation of p53 at the lysine residue 120, resulting in increased p53 transcriptional activity with the induction of PUMA and BAX. 22,23 Several studies have reported that the acetylase activity of Tip60 is enhanced by various stresses such as ER stress, serum deprivation, and DNA damage, including damage due to ionizing radiation and UV irradiation. 24...

Adenine nucleotide translocases (ANTs) transport ADP and ATP through mitochondrial inner membrane, thus playing an essential role for energy metabolism of eukaryotic cells. Mice have three ANT paralogs, Ant1 (Slc25a4), Ant2 (Slc25a5) and Ant4 (Slc25a31), which are expressed in a tissue-dependent manner. While knockout mice have been characterized with Ant1 and Ant4 genes, which resulted in exercise intolerance and male infertility, respectively, the role of the ubiquitously expressed Ant2 gene in animal development has not been fully demonstrated. Here, we generated Ant2 hypomorphic mice by targeted disruption of the gene, in which Ant2 expression is largely depleted. The mice showed apparently normal embryonic development except pale phenotype along with a reduced birth rate. However, postnatal growth was severely retarded with macrocytic anemia, B lymphocytopenia, lactic acidosis and bloated stomach, and died within 4 weeks. Ant2 depletion caused anemia in a cell-autonomous manner by maturation arrest of erythroid precursors with increased reactive oxygen species and premature deaths. B-lymphocyte development was similarly affected by Ant2 depletion, and splenocytes showed a reduction in maximal respiration capacity and cellular ATP levels as well as an increase in cell death accompanying mitochondrial permeability transition pore opening. In contrast, myeloid, megakaryocyte and T-lymphocyte lineages remained apparently intact. Erythroid and B-cell development may be particularly vulnerable to Ant2 depletion-mediated mitochondrial dysfunction and oxidative stress.

We identified five FRMD7 mutations in 35% of our infantile nystagmus syndrome cohort, expanding its mutational spectrum. The missense mutation c.875T>C may be a common mutation arisen from the founder effect in Korea. Optic nerve dysplasia associated with FRMD7 mutations suggests that the abnormal development of afferent visual systems may affect neural circuitry within the oculomotor system.