Autophagy is a membrane-mediated intracellular degradation system. The serine/threonine kinase Atg1 plays an essential role in autophagosome formation. However, the role of the mammalian Atg1 homologues UNC-51–like kinase (ULK) 1 and 2 are not yet well understood. We found that murine ULK1 and 2 localized to autophagic isolation membrane under starvation conditions. Kinase-dead alleles of ULK1 and 2 exerted a dominant-negative effect on autophagosome formation, suggesting that ULK kinase activity is important for autophagy. We next screened for ULK binding proteins and identified the focal adhesion kinase family interacting protein of 200 kD (FIP200), which regulates diverse cellular functions such as cell size, proliferation, and migration. We found that FIP200 was redistributed from the cytoplasm to the isolation membrane under starvation conditions. In FIP200-deficient cells, autophagy induction by various treatments was abolished, and both stability and phosphorylation of ULK1 were impaired. These results suggest that FIP200 is a novel mammalian autophagy factor that functions together with ULKs.

/pdf/fip200-a-ulk-interacting-protein-is-required-for-4qx4zzhakt.pdf

FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells

Cytoskeletal microtubules have been proposed to influence cell shape and mechanics based on their ability to resist large-scale compressive forces exerted by the surrounding contractile cytoskeleton. Consistent with this, cytoplasmic microtubules are often highly curved and appear buckled because of compressive loads. However, the results of in vitro studies suggest that microtubules should buckle at much larger length scales, withstanding only exceedingly small compressive forces. This discrepancy calls into question the structural role of microtubules, and highlights our lack of quantitative knowledge of the magnitude of the forces they experience and can withstand in living cells. We show that intracellular microtubules do bear large-scale compressive loads from a variety of physiological forces, but their buckling wavelength is reduced significantly because of mechanical coupling to the surrounding elastic cytoskeleton. We quantitatively explain this behavior, and show that this coupling dramatically increases the compressive forces that microtubules can sustain, suggesting they can make a more significant structural contribution to the mechanical behavior of the cell than previously thought possible.

/pdf/microtubules-can-bear-enhanced-compressive-loads-in-living-11gktjfmzy.pdf

Microtubules can bear enhanced compressive loads in living cells because of lateral reinforcement

Focal adhesion kinase family interacting protein of 200 kD (FIP200) has been shown to regulate diverse cellular functions such as cell size, proliferation, and migration in vitro. However, the function of FIP200 in vivo has not been investigated. We show that targeted deletion of FIP200 in the mouse led to embryonic death at mid/late gestation associated with heart failure and liver degeneration. We found that FIP200 knockout (KO) embryos show reduced S6 kinase activation and cell size as a result of increased tuberous sclerosis complex function. Furthermore, FIP200 KO embryos exhibited significant apoptosis in heart and liver. Consistent with this, FIP200 KO mouse embryo fibroblasts and liver cells showed increased apoptosis and reduced c-Jun N-terminal kinase phosphorylation in response to tumor necrosis factor (TNF) α stimulation, which might be mediated by FIP200 interaction with apoptosis signal–regulating kinase 1 (ASK1) and TNF receptor–associated factor 2 (TRAF2), regulation of TRAF2–ASK1 interaction, and ASK1 phosphorylation. Together, our results reveal that FIP200 functions as a regulatory node to couple two important signaling pathways to regulate cell growth and survival during mouse embryogenesis.

/pdf/role-of-fip200-in-cardiac-and-liver-development-and-its-13kdb6ljyn.pdf

Role of FIP200 in cardiac and liver development and its regulation of TNFα and TSC–mTOR signaling pathways

FIP200 is required for the cell-autonomous maintenance of fetal hematopoietic stem cells.

Childhood Leukemias: Acute lymphoblastic leukemia

RB1-inducible coiled-coil 1 (RB1CC1) is a novel molecule implicated in the regulation of RB1 (retinoblastoma 1) expression. However, information about the RB1CC1 gene is limited and its function remains somewhat obscure. The present study analyzes the expression and promoter activities of RB1CC1 in developing murine and human tissues. Rb1cc1 was abundantly expressed from an early stage of the mouse embryo throughout development. Immunohistochemical analyses revealed that Rb1cc1 was ubiquitous in the mouse, rather than in the human embryo, especially in the musculoskeletal system, heart and neural tissues. Promoter activity was highest in a region located about 300 bp immediately upstream of exon 1 in both the mouse and human RB1CC1 genes, suggesting that this region is a core promoter. The promoter activity of RB1CC1 was generally higher in mice than in humans, and suppressive with intron 1, especially in humans. These results suggested that more Rb1cc1 is expressed throughout developing murine than in human tissues, and that RB1CC1 expression is controlled more stringently by modification at intron 1 in humans than in mice.

Expression and regulation of RB1CC1 in developing murine and human tissues.

Chemotherapy for malignant neoplasms sometimes causes unconjugated hyperbilirubinemia in the absence of liver dysfunction. We analyzed the association of chemotherapy-induced hyperbilirubinemia with mutations of the bilirubin uridine-5'-diphosphate (UDP)-glucuronosyltransferase gene (UGT1A1) from two leukemic patients in whom chemotherapy resulted in a hyperbilirubinemic response. We isolated genomic DNA from peripheral blood samples and amplified UGT1A1 by polymerase chain reaction. The amplified DNA fragments were analyzed by direct sequencing. The genes of the two patients revealed an identical heterozygous missense mutation in exon 1 (211G-->A: G71R). This UGT1A1 mutation may be the basis of chemotherapy-induced unconjugated hyperbilirubinemia.

Chemotherapy-induced unconjugated hyperbilirubinemia caused by a mutation of the bilirubin uridine-5'-diphosphate-glucuronosyltransferase gene.

Figure 1 Brain magnetic resonance imaging (MRI) by fluidattenuated inversion recovery (FLAIR) images (TI/TR/TE 2,200/ 10,002/142 ms). A: Case 1 at 7 days of age. Note the bilateral periventricular hypointensity lesions in the frontal region (arrows). B: Case 2 at 4 months of age. The white matter lesions were more extensive in the frontal region (arrows) than in the occipital region (arrowheads). Tomoyuki Takano1,*, Mayumi Morimoto1, Noriko Bamba1, Yoshihiro Takeuchi1 and Masaki Ohno2

Frontal-dominant white matter lesions following congenital rubella and cytomegalovirus infection

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Papers

Expression and regulation of RB1CC1 in developing murine and human tissues.

Chemotherapy-induced unconjugated hyperbilirubinemia caused by a mutation of the bilirubin uridine-5'-diphosphate-glucuronosyltransferase gene.

Frontal-dominant white matter lesions following congenital rubella and cytomegalovirus infection