Max Activity Research Articles

MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues.

MAX inactivation deregulates multiple transcription factors to induce neuroendocrine cancers.

Functional interplay between c-Myc and Max in B lymphocyte differentiation.

The Myc family of oncogenic transcription factors regulates myriad cellular functions. Myc proteins contain a basic region/helix-loop-helix/leucine zipper domain that mediates DNA binding and heterodimerization with its partner Max. Among the Myc proteins, c-Myc is the most widely expressed and relevant in primary B lymphocytes. There is evidence suggesting that c-Myc can perform some of its functions in the absence of Max in different cellular contexts. However, the functional in vivo interplay between c-Myc and Max during B lymphocyte differentiation is not well understood. Using in vivo and ex vivo models, we show that while c-Myc requires Max in primary B lymphocytes, several key biological processes, such as cell differentiation and DNA replication, can initially progress without the formation of c-Myc/Max heterodimers. We also describe that B lymphocytes lacking Myc, Max, or both show upregulation of signaling pathways associated with the B-cell receptor. These data suggest that c-Myc/Max heterodimers are not essential for the initiation of a subset of important biological processes in B lymphocytes, but are required for fine-tuning the initial response after activation.

What is New in Gastrointestinal Stromal Tumor?

The classification "gastrointestinal stromal tumor" (GIST) became commonplace in the 1990s and since that time various advances have characterized the GIST lineage of origin, tyrosine kinase mutations, and mechanisms of response and resistance to targeted therapies. In addition to tyrosine kinase mutations and their constitutive activation of downstream signaling pathways, GISTs acquire a sequence of chromosomal aberrations. These include deletions of chromosomes 14q, 22q, 1p, and 15q, which harbor putative tumor suppressor genes required for stepwise progression from microscopic, preclinical forms of GIST (microGIST) to clinically relevant tumors with malignant potential. Recent advances extend our understanding of GIST biology beyond that of the oncogenic KIT/PDGFRA tyrosine kinases and beyond mechanisms of KIT/PDGFRA-inhibitor treatment response and resistance. These advances have characterized ETV1 as an essential interstitial cell of Cajal-GIST transcription factor in oncogenic KIT signaling pathways, and have characterized the biologically distinct subgroup of succinate dehydrogenase deficient GIST, which are particularly common in young adults. Also, recent discoveries of MAX and dystrophin genomic inactivation have expanded our understanding of GIST development and progression, showing that MAX inactivation is an early event fostering cell cycle activity, whereas dystrophin inactivation promotes invasion and metastasis.

MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation

KIT, PDGFRA, NF1 and SDH mutations are alternate initiating events, fostering hyperplasia in gastrointestinal stromal tumours (GISTs), and additional genetic alterations are required for progression to malignancy. The most frequent secondary alteration, demonstrated in ∼70% of GISTs, is chromosome 14q deletion. Here we report hemizygous or homozygous inactivating mutations of the chromosome 14q MAX gene in 16 of 76 GISTs (21%). We find MAX mutations in 17% and 50% of sporadic and NF1-syndromic GISTs, respectively, and we find loss of MAX protein expression in 48% and 90% of sporadic and NF1-syndromic GISTs, respectively, and in three of eight micro-GISTs, which are early GISTs. MAX genomic inactivation is associated with p16 silencing in the absence of p16 coding sequence deletion and MAX induction restores p16 expression and inhibits GIST proliferation. Hence, MAX inactivation is a common event in GIST progression, fostering cell cycle activity in early GISTs.

Abstract A35: MAX inactivation in small cell lung cancer disrupts the MYC-SWI/SNF programs and is synthetic lethal with BRG1

Abstract Our knowledge of small cell lung cancer (SCLC) genetics is still very limited, amplification of L-MYC , N-MYC , and C-MYC being some of the well-established genealterations. Here, we report our discovery of tumor-specifi c inactivation of the MYC-associated factorX gene, MAX , in SCLC. MAX inactivation is mutually exclusive with alterations of MYC and BRG1 , thelatter coding for an ATPase of the switch/sucrose nonfermentable (SWI/SNF) complex. We demonstratethat BRG1 regulates the expression of MAX through direct recruitment to the MAX promoter, and thatdepletion of BRG1 strongly hinders cell growth, specifi cally in MAX-defi cient cells, heralding a syntheticlethal interaction. Furthermore, MAX requires BRG1 to activate neuroendocrine transcriptional programsand to upregulate MYC targets, such as glycolysis-related genes. Finally, inactivation of the MAXdimerization protein, MGA, was also observed in both non–small cell lung cancer and SCLC. Our resultsprovide evidence that an aberrant SWI/SNF–MYC network is essential for lung cancer development. SIGNIFICANCE: We discovered that the MYC-associated factor X gene, MAX , is inactivated in SCLCs.Furthermore, we revealed a preferential toxicity of the inactivation of the chromatin remodeler BRG1in MAX-defi cient lung cancer cells, which opens novel therapeutic possibilities for the treatment ofpatients with SCLC with MAX-defi cient tumors. Citation Format: Manuel Torres-Diz, Octavio A. Romero, Eva Pros, Suvi Savola, Antonio Gomez, Sebastian Moran, Luis M. Montuenga, Jun Yokota, Montse Sanchez-Cespedes. MAX inactivation in small cell lung cancer disrupts the MYC-SWI/SNF programs and is synthetic lethal with BRG1. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A35.

Abstract 2477: Max inactivation in small cell lung cancer disrupts the MYC-SWI/SNF programs and is synthetic lethal with BRG1

Abstract Our knowledge of small cell lung cancer (SCLC) genetics is still very limited, amplification of L-MYC, N-MYC and C-MYC being some of the well established gene alterations. Here, we report our discovery of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in SCLC. This is mutually exclusive with alterations at MYC and BRG1, the latter coding for an ATPase of the SWI/SNF complex. We demonstrate that BRG1 regulates the expression of MAX through direct recruitment to the MAX promoter, and that depletion of BRG1 strongly hinders cell growth, specifically in MAX-deficient cells, heralding a synthetic lethal interaction. Furthermore, MAX requires BRG1 to activate neuroendocrine transcriptional programs and to up-regulate MYC-targets, such as glycolytic-related genes. Finally, we observed genetic inactivation of the MAX dimerization protein, MGA, in lung cancers with wild type components of the SWI/SNF or MYC pathways. Our results provide evidence that an aberrant SWI/SNF-MYC network is essential for lung cancer development. Citation Format: Octavio A. Romero-Ferraro, Manuel Torres-Diz, Eva Pros, Antonio Gomez Moruno, Sebastian Moran Salama, Suvi Savola, Luis M. Montuenga, Ruben Pio, Jun Yokota, Montse Sanchez-Cespedes. Max inactivation in small cell lung cancer disrupts the MYC-SWI/SNF programs and is synthetic lethal with BRG1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2477. doi:10.1158/1538-7445.AM2014-2477

MAX Inactivation in Small Cell Lung Cancer Disrupts MYC–SWI/SNF Programs and Is Synthetic Lethal with BRG1

Our knowledge of small cell lung cancer (SCLC) genetics is still very limited, amplification of L-MYC, N-MYC, and C-MYC being some of the well-established gene alterations. Here, we report our discovery of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in SCLC. MAX inactivation is mutually exclusive with alterations of MYC and BRG1, the latter coding for an ATPase of the switch/sucrose nonfermentable (SWI/SNF) complex. We demonstrate that BRG1 regulates the expression of MAX through direct recruitment to the MAX promoter, and that depletion of BRG1 strongly hinders cell growth, specifically in MAX-deficient cells, heralding a synthetic lethal interaction. Furthermore, MAX requires BRG1 to activate neuroendocrine transcriptional programs and to upregulate MYC targets, such as glycolysis-related genes. Finally, inactivation of the MAX dimerization protein, MGA, was also observed in both non-small cell lung cancer and SCLC. Our results provide evidence that an aberrant SWI/SNF-MYC network is essential for lung cancer development.

Markierung von kleinen bodentieren durch fütterung mit 14C-markierter glukose

For investigations of the movement of spring-tails (Collembola) (small soil animals of about 1·5 mm length) in soil the animals were radioactive labelled internally by feeding for several days 14C-glucose added to the food (activity max 1·0 × 10 −2 μCi/animal). At certain time intervals the spring-tails were isolated from soil samples taken at various distances from the place where they were released. The determination of radioactive animals were carried out by autoradiography on X-ray film. This method is much more suitable for the demonstration of small animals which are marked with only low activities of low-energy β-radiation as compared to the commonly used method with GM-counters. The movement of spring-tails in the soil is undirected. Within 5–12 days only few of them migrate up to 50 cm. The greatest part of the animals remains very close to the place of release.

Growth substances in the roots of Vicia faba—II

An extension of previous studies 1 on the auxins of Vicia faba roots has used cellulose and cellulose derivative column chromatography and spectrofluorimetry, for the separation and identification of the components of methanol extracts. Purification of the IAA-like ether-soluble acid auxin has been carried out on DEAE cellulose. Owing to the presence of a fluorescent compound (activation max. 330 mμ, emission max. 445 mμ) in the growth active region of chromatograms, IAA could not be positively identified by its u.v. absorption or fluorescent behaviour but cannot be present in quantities greater than 2–5 μg/kg fresh weight of root material. The accompanying fluorescent material may be an auxin very closely related to the “citrus auxin” of Khalifah et al. 2 In the water-soluble ether-insoluble fraction, tryptophan and 3,4-dihydroxy-phenylalanine (DOPA) have been unambiguously demonstrated and accurately estimated to be present in concentrations of 12 mg and 20 mg/kg fresh weight of root respectively. Tryptophan may contribute most, if not all, the auxin activity to the zone on the chromatogram corresponding to WP( i) in pea roots and P 1 previously reported for Vicia roots. Other substances, some probably indoles, are present in the zone but have not been identified. Three other auxin zones (corresponding to WP( ii), WP( iii) and WP( iv) in pea roots) have been shown to contain neutral and basic substances, probably indoles, but not yet identifiable by their fluorescent characteristics. The fact that mild oxidation of DOPA with silver oxide produces substances with auxin activity and properties resembling those of the water-soluble components suggests that the latter may be partly artefacts of DOPA oxidation during extraction and chromatography.