Editorials Reviews Reviews News and Views Merlins wizardry

  • Slides: 45
Download presentation

Editorials

Editorials

Reviews

Reviews

Reviews

Reviews

News and Views Merlin's wizardry guides cohesive migration - pp 212 - 213 Ansgar

News and Views Merlin's wizardry guides cohesive migration - pp 212 - 213 Ansgar Zoch & Helen Morrison Cells often migrate in tightly connected groups with coordinated movement and polarity. The collective migration of epithelial cell sheets is now shown to be mediated by a signalling axis that involves the merlin tumour-suppressor protein, the tight-junction-associated angiomotin– Rich 1 complex and the Rac 1 small GTPase. Huntingtin facilitates selective autophagy - pp 214 - 215 Amir Gelman, Moran Rawet-Slobodkin & Zvulun Elazar Selective autophagy is essential for maintaining cellular homeostasis under different growth conditions. Huntingtin, mutated versions of which have been implicated in Huntington disease, is now shown to act as a scaffold protein that couples the induction of autophagy and the selective recruitment of cargo into autophagosomes.

Article AMBRA 1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation

Article AMBRA 1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation Valentina Cianfanelli, 1, 2, Claudia Fuoco, 3, Mar Lorente, 4, 5, Maria Salazar, 4, 5, n 1 Fabio Quondamatteo, 6, Pier Federico Gherardini, 3, n 1 Daniela De Zio, 1, Francesca Nazio, 2, Manuela Antonioli, 3, 7, Melania D’Orazio, 3, Tatjana Skobo, 8, Matteo Bordi, 2, Mikkel Rohde, 9, Luisa Dalla Valle, 8, Manuela Helmer-Citterich, 3, Christine Gretzmeier, 10, 11, Joern Dengjel, 10, 11, Gian Maria Fimia, 7, 12, Mauro Piacentini, 3, 7, Sabrina Di Bartolomeo, 3, Guillermo Velasco 4, 5, & Francesco Cecconi 1, 2, 3, Inhibition of a main regulator of cell metabolism, the protein kinase m. TOR, induces autophagy and inhibits cell proliferation. However, the molecular pathways involved in the cross-talk between these two m. TOR-dependent cell processes are largely unknown. Here we show that the scaffold protein AMBRA 1, a member of the autophagy signalling network and a downstream target of m. TOR, regulates cell proliferation by facilitating the dephosphorylation and degradation of the proto-oncogene c-Myc. We found that AMBRA 1 favours the interaction between c-Myc and its phosphatase PP 2 A and that, when m. TOR is inhibited, it enhances PP 2 A activity on this specific target, thereby reducing the cell division rate. As expected, such a deregulation of c-Myc correlates with increased tumorigenesis in AMBRA 1 -defective systems, thus supporting a role for AMBRA 1 as a haploinsufficient tumour suppressor gene.

Article Expansion of stem cells counteracts age-related mammary regression in compound Timp 1/Timp 3

Article Expansion of stem cells counteracts age-related mammary regression in compound Timp 1/Timp 3 null mice Hartland W. Jackson, 1, 2, Paul Waterhouse, 2, Ankit Sinha, 1, 2, Thomas Kislinger, 1, 2, Hal K. Berman 2, 3, & Rama Khokha Age is the primary risk factor for breast cancer in women. Bipotent basal stem cells actively maintain the adult mammary ductal tree, but with age tissues atrophy. We show that cellextrinsic factors maintain the adult stem cell pool during ageing and dictate tissue stoichiometry. Mammary stem cells spontaneously expand more than 11 -fold in virgin adult female mice lacking specific genes for TIMPs, the natural metalloproteinase inhibitors. Compound Timp 1/Timp 3 null glands exhibit Notch activation and accelerated gestational differentiation. Proteomics of mutant basal cells uncover altered cytoskeletal and extracellular protein repertoires, and we identify aberrant mitotic spindle orientation in these glands, a process that instructs asymmetric cell division and fate. We find that progenitor activity normally declines with age, but enriched stem/progenitor pools prevent tissue regression in Timp mutant mammary glands without affecting carcinogen-induced cancer susceptibility. Thus, improved stem cell content can extend mouse mammary tissue lifespan without altering cancer risk in this mouse model.

Article Huntingtin functions as a scaffold for selective macroautophagy Yan-Ning Rui, 1, n 1

Article Huntingtin functions as a scaffold for selective macroautophagy Yan-Ning Rui, 1, n 1 Zhen Xu, 1, n 1 Bindi Patel, 2, n 1 Zhihua Chen, 1, Dongsheng Chen, 1, Antonio Tito, 1, 3, Gabriela David, 4, Yamin Sun, 1, Erin F. Stimming, 5, Hugo J. Bellen, 4, 6, 7, Ana Maria Cuervo 2, 8, 9, & Sheng Zhang Selective macroautophagy is an important protective mechanism against diverse cellular stresses. In contrast to the well-characterized starvation-induced autophagy, the regulation of selective autophagy is largely unknown. Here, we demonstrate that Huntingtin, the Huntington disease gene product, functions as a scaffold protein for selective macroautophagy but it is dispensable for non-selective macroautophagy. In Drosophila, Huntingtin genetically interacts with autophagy pathway components. In mammalian cells, Huntingtin physically interacts with the autophagy cargo receptor p 62 to facilitate its association with the integral autophagosome component LC 3 and with Lys-63 -linked ubiquitin-modified substrates. Maximal activation of selective autophagy during stress is attained by the ability of Huntingtin to bind ULK 1, a kinase that initiates autophagy, which releases ULK 1 from negative regulation by m. TOR. Our data uncover an important physiological function of Huntingtin and provide a missing link in the activation of selective macroautophagy in metazoans.

Article Reduced adenosine-to-inosine mi. R-455 -5 p editing promotes melanoma growth and metastasis Einav

Article Reduced adenosine-to-inosine mi. R-455 -5 p editing promotes melanoma growth and metastasis Einav Shoshan, 1, n 1 Aaron K. Mobley, 1, n 1 Russell R. Braeuer, 1, Takafumi Kamiya, 1, Li Huang, 1, Mayra E. Vasquez, 1, Ahmad Salameh, 2, Ho Jeong Lee, 1, Sun Jin Kim, 1, Cristina Ivan, 3, Guermarie Velazquez-Torres, 1, Ka Ming Nip, 4, Kelsey Zhu, 4, Denise Brooks, 4, Steven J. M. Jones, 4, Inanc Birol, 4, Maribel Mosqueda, 5, Yu-ye Wen, 5, Agda Karina Eterovic, 5, Anil K. Sood, 1, 3, Patrick Hwu, 6, Jeffrey E. Gershenwald, 7, A. Gordon Robertson, 4, George A. Calin, 8, Gal Markel, 9, 10, Isaiah J. Fidler 1, & Menashe Bar-Eli 1, Although recent studies have shown that adenosine-to-inosine (A-to-I) RNA editing occurs in micro. RNAs (mi. RNAs), its effects on tumour growth and metastasis are not well understood. We present evidence of CREB-mediated low expression of ADAR 1 in metastatic melanoma cell lines and tumour specimens. Re-expression of ADAR 1 resulted in the suppression of melanoma growth and metastasis in vivo. Consequently, we identified three mi. RNAs undergoing A-to-I editing in the weakly metastatic melanoma but not in strongly metastatic cell lines. One of these mi. RNAs, mi. R-455 -5 p, has two A-to-I RNA-editing sites. The biological function of edited mi. R-455 -5 p is different from that of the unedited form, as it recognizes a different set of genes. Indeed, wild-type mi. R-455 -5 p promotes melanoma metastasis through inhibition of the tumour suppressor gene CPEB 1. Moreover, wild-type mi. R-455 enhances melanoma growth and metastasis in vivo, whereas the edited form inhibits these features. These results demonstrate a previously unrecognized role for RNA editing in melanoma progression.

Article FBXW 7 modulates cellular stress response and metastatic potential through HSF 1 posttranslational

Article FBXW 7 modulates cellular stress response and metastatic potential through HSF 1 posttranslational modification Nikos Kourtis, 1, 2, n 1 Rana S. Moubarak, 3, 4, n 1 Beatriz Aranda-Orgilles, 1, 2, Kevin Lui, 4, 5, Iraz T. Aydin, 6, Thomas Trimarchi, 1, 2, Farbod Darvishian, 3, 4, Christine Salvaggio, 4, 5, Judy Zhong, 4, 7, 8, Kamala Bhatt, 1, 2, Emily I. Chen, 9, Julide T. Celebi, 6, Charalampos Lazaris, 1, 2, 10, Aristotelis Tsirigos, 1, 10, Iman Osman, 4, 5, Eva Hernando 3, 4, & Iannis Aifantis Heat-shock factor 1 (HSF 1) orchestrates the heat-shock response in eukaryotes. Although this pathway has evolved to help cells adapt in the presence of challenging conditions, it is coopted in cancer to support malignancy. However, the mechanisms that regulate HSF 1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase FBXW 7α interacts with HSF 1 through a conserved motif phosphorylated by GSK 3β and ERK 1. FBXW 7α ubiquitylates HSF 1 and loss of FBXW 7α results in impaired degradation of nuclear HSF 1 and defective heat-shock response attenuation. FBXW 7α is either mutated or transcriptionally downregulated in melanoma and HSF 1 nuclear stabilization correlates with increased metastatic potential and disease progression. FBXW 7α deficiency and subsequent HSF 1 accumulation activates an invasion-supportive transcriptional program and enhances the metastatic potential of human melanoma cells. These findings identify a post-translational mechanism of regulation of the HSF 1 transcriptional program both in the presence of exogenous stress and in cancer.

Article

Article

Abstract ERBB 3, a member of the EGFR family of receptor tyrosine kinases, has

Abstract ERBB 3, a member of the EGFR family of receptor tyrosine kinases, has been implicated in activation of the PI 3 K pathway in human lung adenocarcinomas driven by EGFR mutations. We investigated the contribution of ERBB 3 to the initiation, progression, and therapeutic response of EGFR-induced lung adenocarcinomas using tetracycline- and tamoxifen-inducible transgenic mouse models. Deletion of Erbb 3 at the time of induction of mutant EGFR had no effect on tumorigenesis, demonstrating that ERBB 3 is not required to initiate tumorigenesis. Tumors that developed in the absence of ERBB 3 remained sensitive to EGFR tyrosine kinase inhibitors and retained activation of the PI 3 K–AKT pathway. Interestingly, acute loss of Erbb 3 suppressed further growth of established EGFR L 858 R-mediated lung tumors. Four weeks after deletion of Erbb 3, the tumors exhibited phosphorylation of EGFR, of the adaptor proteins GAB 1 and GAB 2, and of the downstream signaling molecules AKT and ERK, suggesting that alternative signaling pathways could compensate for loss of Erbb 3. Similar to our observations with mouse tumors, we found that GAB adaptor proteins play a role in ERBB 3 -independent activation of the PI 3 K pathway by mutant EGFR in EGFR-mutant human cell lines. Finally, in such cell lines, increased levels of phosphorylation of ERBB 2 or MET were associated with reduced sensitivity to acute loss of ERBB 3, suggesting remarkable plasticity in the signaling pathways regulated by mutant EGFR with important therapeutic implications. Cancer Res; 75(6); 1035– 45. © 2015 AACR. 1

Abstract Genetic mouse studies suggest that the NF-κB pathway regulator NEMO (also known as

Abstract Genetic mouse studies suggest that the NF-κB pathway regulator NEMO (also known as IKKγ) controls chronic inflammation and carcinogenesis in the liver. However, the molecular mechanisms explaining the function of NEMO are not well defined. Here, we report that overexpression of the cell-cycle regulator p 21 is a critical feature of liver inflammation and carcinogenesis caused by the loss of NEMO Δhepa mice develop chronic hepatitis characterized by increased hepatocyte apoptosis and proliferation that causes the development of fibrosis and hepatocellular carcinoma (HCC), similar to the situation in human liver disease. Having identified p 21 overexpression in this model, we evaluated its role in disease progression and LPS-mediated liver injury in double mutant NEMOΔhepa/p 21−/− mice. Eight-week-old NEMO Δhepa/p 21−/− animals displayed accelerated liver damage that was not associated with alterations in cell-cycle progression or the inflammatory response. However, livers from NEMOΔhepa/p 21−/− mice displayed more severe DNA damage that was further characterized by LPS administration correlating with higher lethality of the animals. This phenotype was attenuated by genetic ablation of the TNF receptor TNF-R 1 in NEMO Δhepa/p 21−/− mice, demonstrating that DNA damage is induced via TNF. One-year-old NEMOΔhepa/p 21−/− mice displayed greater numbers of HCC and severe cholestasis compared with NEMO Δhepa animals. Therefore, p 21 overexpression in NEMO Δhepa animals protects against DNA damage, acceleration of hepatocarcinogenesis, and cholestasis. Taken together, our findings illustrate how loss of NEMO promotes chronic liver inflammation and carcinogenesis, and they identify a novel protective role for p 21 against the generation of DNA

KJ Peroxisome Proliferator-Activated Receptor γ Controls Ingestive Behavior, Agouti -Related Protein, and Neuropeptide Y

KJ Peroxisome Proliferator-Activated Receptor γ Controls Ingestive Behavior, Agouti -Related Protein, and Neuropeptide Y m. RNA in the Arcuate Hypothalamus John T. Garretson 1, 3, Brett J. W. Teubner 2, Kevin L. Grove 4, Almira Vazdarjanova 5, 6, Vitaly Ryu 2, 3, and Timothy J. Bartness 1, 2, 3 1 Neuroscience Institute, 2 Department of Biology, and 3 Center for Obesity Reversal, Georgia State University, Atlanta, Georgia 30303, 4 Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97006, 5 Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia 30912, and 6 Charlie Norwood Veterans Administration Medical Center, Augusta, Georgia 30901 Abstract Peroxisome proliferator-activated receptor γ (PPARγ) is clinically targeted for type II diabetes treatment; however, rosiglitazone (ROSI), a PPARγ agonist, increases food intake and body/fat mass as side-effects. Mechanisms for these effects and the role of PPARγ in feeding are not understood. Therefore, we tested this role in Siberian hamsters, a model of human energy balance, and C 57 BL/6 mice. We tested the following: (1) how ROSI and/or GW 9662 (2 -chloro-5 -nitro-N-phenylbenzamide; PPARγ antagonist) injected intraperitoneally or into the third ventricle (3 V) affected Siberian hamster feeding behaviors; (2) whether food deprivation (FD) co-increases agouti-related protein (Ag. RP) and PPARγ m. RNA expression in Siberian hamsters and mice; (3) whether intraperitoneally administered ROSI increases Ag. RP and NPY in ad libitum-fed animals; (4) whether intraperitoneally administered PPARγ antagonism blocks FD-induced increases in Ag. RP and NPY; and finally, (5) whether intraperitoneally administered PPARγ modulation affects plasma ghrelin. Third ventricular and intraperitoneally administered ROSI increased food hoarding and intake for 7 d, an effect attenuated by 3 V GW 9662, and also prevented (intraperitoneal) FD-induced feeding. FD hamsters and mice increased Ag. RP within the arcuate hypothalamic nucleus with concomitant increases in PPARγ exclusively within Ag. RP/NPY neurons. ROSI increased Ag. RP and NPY similarly to FD, and GW 9662 prevented FD-induced increases in Ag. RP and NPY in both species. Neither ROSI nor GW 9662 affected plasma ghrelin. Thus, we demonstrated that PPARγ activation is sufficient to trigger food hoarding/intake, increase Ag. RP/NPY, and possibly is necessary for FD-induced increases in feeding and Ag. RP/NPY. These findings provide initial evidence that FD-induced increases in Ag. RP/NPY may be a direct PPARγ-dependent process that controls ingestive behaviors.

KJ

KJ

KJ

KJ

KJ

KJ

KJ

KJ

Tumor cell migration screen identifies SRPK 1 as breast cancer metastasis determinant Wies van

Tumor cell migration screen identifies SRPK 1 as breast cancer metastasis determinant Wies van Roosmalen 1, Sylvia E. Le Dévédec 1, Ofra Golani 2, Marcel Smid 3, Irina Pulyakhina 4, Annemieke M. Timmermans 3, Maxime P. Look 3, Di Zi 1, Chantal Pont 1, Marjo de Graauw 1, Suha Naffar-Abu-Amara 5, Catherine Kirsanova 6, Gabriella Rustici 6, Peter A. C. ‘t Hoen 4, John W. M. Martens 3, John A. Foekens 3, Benjamin Geiger 5 and Bob van de Water 1 Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands. Tumor cell migration is a key process for cancer cell dissemination and metastasis that is controlled by signal-mediated cytoskeletal and cell matrix adhesion remodeling. Using a phagokinetic track assay with migratory H 1299 cells, we performed an si. RNA screen of almost 1, 500 genes encoding kinases/phosphatases and adhesome- and migration-related proteins to identify genes that affect tumor cell migration speed and persistence. Thirty candidate genes that altered cell migration were validated in live tumor cell migration assays. Eight were associated with metastasis-free survival in breast cancer patients, with integrin β 3–binding protein (ITGB 3 BP), MAP 3 K 8, NIMA-related kinase (NEK 2), and SHC-transforming protein 1 (SHC 1) being the most predictive. Examination of genes that modulate migration indicated that SRPK 1, encoding the splicing factor kinase SRSF protein kinase 1, is relevant to breast cancer outcomes, as it was highly expressed in basal breast cancer. Furthermore, high SRPK 1 expression correlated with poor breast cancer disease outcome and preferential metastasis to the lungs and brain. In 2 independent murine models of breast tumor metastasis, stable sh. RNAbased SRPK 1 knockdown suppressed metastasis to distant organs, including lung, liver, and spleen, and inhibited focal adhesion reorganization. Our study provides comprehensive information on the molecular determinants of tumor cell migration and suggests that SRPK 1 has potential as a drug target for limiting breast cancer metastasis.

[Science] 20 MARCH 2015 VOL 347, ISSUE 6228, PAGES 1285 -1388

[Science] 20 MARCH 2015 VOL 347, ISSUE 6228, PAGES 1285 -1388

[Science] 20 MARCH 2015 VOL 347, ISSUE 6228, PAGES 1285 -1388

[Science] 20 MARCH 2015 VOL 347, ISSUE 6228, PAGES 1285 -1388

[Science] 20 MARCH 2015 VOL 347, ISSUE 6228, PAGES 1285 -1388

[Science] 20 MARCH 2015 VOL 347, ISSUE 6228, PAGES 1285 -1388

[Science] 20 MARCH 2015 VOL 347, ISSUE 6228, PAGES 1285 -1388

[Science] 20 MARCH 2015 VOL 347, ISSUE 6228, PAGES 1285 -1388