Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la protéine MAD2L2 régule l'activité de réparation de l'ADN

MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5' end resection

Boersma, Vera ; Moatti, Nathalie ; Segura-Bayona, Sandra ; Peuscher, Marieke H. ; van der Torre, Jaco ; Wevers, Brigitte A. ; Orthwein, Alexandre ; Durocher, Daniel ; Jacobs, Jacqueline J. L.

Appropriate repair of DNA lesions and the inhibition of DNA repair activities at telomeres are crucial to prevent genomic instability. By fuelling the generation of genetic alterations and by compromising cell viability, genomic instability is a driving force in cancer and ageing. Here we identify MAD2L2 (also known as MAD2B or REV7) through functional genetic screening as a novel factor controlling DNA repair activities at mammalian telomeres. We show that MAD2L2 accumulates at uncapped [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels un variant de la cycline D1 exerce une fonction d'oncogène

Consequence of the tumor-associated conversion to cyclin D1b

Augello, Michael A. ; Berman-Booty, Lisa D. ; Carr, Richard ; Yoshida, Akihiro ; Dean, Jeffry L. ; Schiewer, Matthew J. ; Feng, Felix Y. ; Tomlins, Scott A. ; Gao, Erhe ; Koch, Walter J. ; Benovic, Jeffrey L. ; Diehl, John Alan ; Knudsen, Karen E.

Clinical evidence suggests that cyclin D1b, a variant of cyclin D1, is associated with tumor progression and poor outcome. However, the underlying molecular basis was unknown. Here, novel models were created to generate a genetic switch from cyclin D1 to cyclin D1b. Extensive analyses uncovered overlapping but non-redundant functions of cyclin D1b compared to cyclin D1 on developmental phenotypes, and illustrated the importance of the transcriptional regulatory functions of cyclin D1b in vivo. [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels des mutations du gène de l'enzyme IDH2 favorisent le développement des cellules souches de leucémie myéloïde aiguë

IDH2 and NPM1 mutations cooperate to activate Hoxa9/Meis1 and hypoxia pathways in acute myeloid leukemia

Ogawara, Yoko ; Takuo Katsumoto, Takuo ; Aikawa, Yukiko ; Shima, Yutaka ; Kagiyama, Yuki ; Soga, Tomoyoshi ; Matsunaga, Hironori ; Seki, Takahiko ; Araki, Kazushi ; Kitabayashi, Issay

IDH1 and IDH2 mutations occur frequently in acute myeloid leukemia (AML) and other cancers. The mutant IDH enzymes convert α-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), which dysregulates a set of α-KG-dependent dioxygenases. To determine whether mutant IDH enzymes are valid targets for cancer therapy, we created a mouse model of AML in which mice were transplanted with nucleophosmin1 (NPM1)+/- hematopoietic stem/progenitor cells co-transduced with four mutant genes [...]

Cet article passe en revue les travaux récents sur les interactions entre nerfs et cellules cancéreuses dans le micro-environnement des tumeurs solides

Nerve–Cancer Cell Cross-talk: A Novel Promoter of Tumor Progression

Jobling, Phillip ; Pundavela, Jay ; Oliveira, Sonia M.R. ; Roselli, Séverine ; Walker, Marjorie M. ; Hondermarck, Hubert

Recent studies have revealed the essential role played by nerves in tumor progression. Nerves have been shown to infiltrate the tumor microenvironment and actively stimulate cancer cell growth and dissemination. This mechanism involves the release of neurotransmitters, such as catecholamines and acetylcholine, directly into the vicinity of cancer and stromal cells to activate corresponding membrane receptors. Conversely, the secretion of neurotrophic growth factors by cancer cells drives the [...]

Cet article passe en revue les travaux récents sur le rôle du système immunitaire inné et des processus inflammatoires dans le développement et la progression d'un cancer

Balancing the innate immune system in tumor development

Hagerling, Catharina ; Casbon, Amy-Jo ; Werb, Zena

Cells of the innate immune system have a dual role in cancer development in both tumor initiation and progression. Innate immune cells can, on the one hand, aid malignant transformation and tumor outgrowth and, on the other hand, prevent tumor progression. The innate immune system has the ability to tune the inflammatory response and is a key player in cancer-related inflammation, which can precede the development of malignancy or be induced by oncogenic changes promoting a protumor [...]

Menée in vitro et in vivo sur des modèles de mélanome, cette étude met en évidence des mécanismes par lesquels, via sa régulation par un micro-environnement tumoral hypoxique, un variant d'une "protéine d'échafaudage" (AKAP12v2) favorise les processus invasif et métastatique

Hypoxic induction of AKAP12 variant 2 shifts PKA-mediated protein phosphorylation to enhance migration and metastasis of melanoma cells

Finger, Elizabeth C. ; Castellini, Laura ; Rankin, Erinn B. ; Vilalta, Marta ; Krieg, Adam J. ; Jiang, Dadi ; Banh, Alice ; Zundel, Wayne ; Powell, Marianne Broome ; Giaccia, Amato J.

Scaffold proteins are critical hubs within cells that have the ability to modulate upstream signaling molecules and their downstream effectors to fine-tune biological responses. Although they can serve as focal points for association of signaling molecules and downstream pathways that regulate tumorigenesis, little is known about how the tumor microenvironment affects the expression and activity of scaffold proteins. This study demonstrates that hypoxia, a common element of solid tumors [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels une surexpression de la protéine SPINK1 favorise la prolifération des cellules cancéreuses dans le côlon

SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-associated Cancer

Ida, Satoshi ; Ozaki, Nobuyuki ; Araki, Kimi ; Hirashima, Kotaro ; Zaitsu, Yoko ; Taki, Katsunobu ; Sakamoto , Yasuo ; Miyamoto, Yuji ; Oki, Eiji ; Morita, Masaru ; Watanabe, Masayuki ; Maehara, Yoshihiko ; Yamamura, Ken-ichi ; Baba, Hideo ; Ohmuraya, Masaki

Colorectal cancer (CRC) is a major cause of deaths due to cancer; therefore, research into its etiology is urgently needed. Although it is clear that chronic inflammation is a risk factor for CRC, the details remains uncertain. Serine protease inhibitor Kazal type 1 (SPINK1) is mainly produced in pancreatic acinar cells. However, SPINK1 is expressed in various cancers and in inflammatory states such as colon cancer and inflammatory bowel disease. There are structural similarities between SPINK1 [...]