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Articles by T. W. Mak
Total Records ( 4 ) for T. W. Mak
  M. T Wilhelm , A Rufini , M. K Wetzel , K Tsuchihara , S Inoue , R Tomasini , A Itie Youten , A Wakeham , M Arsenian Henriksson , G Melino , D. R Kaplan , F. D Miller and T. W. Mak

Mice with a complete deficiency of p73 have severe neurological and immunological defects due to the absence of all TAp73 and Np73 isoforms. As part of our ongoing program to distinguish the biological functions of these isoforms, we generated mice that are selectively deficient for the Np73 isoform. Mice lacking Np73 (Np73–/– mice) are viable and fertile but display signs of neurodegeneration. Cells from Np73–/– mice are sensitized to DNA-damaging agents and show an increase in p53-dependent apoptosis. When analyzing the DNA damage response (DDR) in Np73–/– cells, we discovered a completely new role for Np73 in inhibiting the molecular signal emanating from a DNA break to the DDR pathway. We found that Np73 localizes directly to the site of DNA damage, can interact with the DNA damage sensor protein 53BP1, and inhibits ATM activation and subsequent p53 phosphorylation. This novel finding may explain why human tumors with high levels of Np73 expression show enhanced resistance to chemotherapy.

  M. W Tusche , L. A Ward , F Vu , D McCarthy , M Quintela Fandino , J Ruland , J. L Gommerman and T. W. Mak

B cell activation factor of the TNF family (BAFF) activates noncanonical nuclear factor B (NF-B) heterodimers that promote B cell survival. We show that although MALT1 is largely dispensable for canonical NF-B signaling downstream of the B cell receptor, the absence of MALT1 results in impaired BAFF-induced phosphorylation of NF-B2 (p100), p100 degradation, and RelB nuclear translocation in B220+ B cells. This corresponds with impaired survival of MALT1–/– marginal zone (MZ) but not follicular B cells in response to BAFF stimulation in vitro. MALT1–/– MZ B cells also express higher amounts of TRAF3, a known negative regulator of BAFF receptor–mediated signaling, and TRAF3 was found to interact with MALT1. Furthermore, phenotypes associated with overexpression of BAFF, including increased MZ B cell numbers, elevated serum immunoglobulin titers, and spontaneous germinal center formation, were found to be dependent on B cell–intrinsic MALT1 expression. Our results demonstrate a novel role for MALT1 in biological outcomes induced by BAFF-mediated signal transduction.

  S Kamizono , G. S Duncan , M. G Seidel , A Morimoto , K Hamada , G Grosveld , K Akashi , E. F Lind , J. P Haight , P. S Ohashi , A. T Look and T. W. Mak

Nuclear factor interleukin-3 (Nfil3; also known as E4-binding protein 4) is a basic region leucine zipper transcription factor that has antiapoptotic activity in vitro under conditions of growth factor withdrawal. To study the role of Nfil3 in vivo, we generated gene-targeted Nfil3-deficient (Nfil3–/–) mice. Nfil3–/– mice were born at normal Mendelian frequency and were grossly normal and fertile. Although numbers of T cells, B cells, and natural killer (NK) T cells were normal in Nfil3–/– mice, a specific disruption in NK cell development resulted in severely reduced numbers of mature NK cells in the periphery. This defect was NK cell intrinsic in nature, leading to a failure to reject MHC class I–deficient cells in vivo and reductions in both interferon production and cytolytic activity in vitro. Our results confirm the specific and essential requirement of Nfil3 for the development of cells of the NK lineage.

  S Gross , R. A Cairns , M. D Minden , E. M Driggers , M. A Bittinger , H. G Jang , M Sasaki , S Jin , D. P Schenkein , S. M Su , L Dang , V. R Fantin and T. W. Mak

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), are present in most gliomas and secondary glioblastomas, but are rare in other neoplasms. IDH1/2 mutations are heterozygous, and affect a single arginine residue. Recently, IDH1 mutations were identified in 8% of acute myelogenous leukemia (AML) patients. A glioma study revealed that IDH1 mutations cause a gain-of-function, resulting in the production and accumulation of 2-hydroxyglutarate (2-HG). Genotyping of 145 AML biopsies identified 11 IDH1 R132 mutant samples. Liquid chromatography-mass spectrometry metabolite screening revealed increased 2-HG levels in IDH1 R132 mutant cells and sera, and uncovered two IDH2 R172K mutations. IDH1/2 mutations were associated with normal karyotypes. Recombinant IDH1 R132C and IDH2 R172K proteins catalyze the novel nicotinamide adenine dinucleotide phosphate (NADPH)–dependent reduction of -ketoglutarate (-KG) to 2-HG. The IDH1 R132C mutation commonly found in AML reduces the affinity for isocitrate, and increases the affinity for NADPH and -KG. This prevents the oxidative decarboxylation of isocitrate to -KG, and facilitates the conversion of -KG to 2-HG. IDH1/2 mutations confer an enzymatic gain of function that dramatically increases 2-HG in AML. This provides an explanation for the heterozygous acquisition of these mutations during tumorigenesis. 2-HG is a tractable metabolic biomarker of mutant IDH1/2 enzyme activity.

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