Disease relevance of ASH1L

• We show here that human achaete-scute homologue-1 (hASH1) is selectively expressed in normal fetal pulmonary neuroendocrine cells, as well as in the diverse range of lung cancers with neuroendocrine features [1].
• ASH1 mRNA was widely detected in normal pituitaries, in all tumour cell lines and in most PA (84%), with measurable levels in corticotroph (5/5) and CNS (9/11) adenomas, and in a significant subset of PA derived from Pit-1 dependent lineages (9/16) [2].
• METHODS: To further elucidate the function and regulation of hASH1 in neuroendocrine tumor differentiation, we used a model of MTC tumor differentiation mediated by the ras/raf-1 signaling pathway [3].
• Downregulation of hASH1 is associated with the retinoic acid-induced differentiation of human neuroblastoma cell lines [4].
• Moreover, studies of small cell carcinoma and non- small cell carcinoma suggest that neuroendocrine differentiation could be regulated by hASH1 [5].

High impact information on ASH1L

• huASH1 protein, a putative transcription factor encoded by a human homologue of the Drosophila ash1 gene, localizes to both nuclei and cell-cell tight junctions [6].
• Using several anti-huASH1 Ab for immunostaining of cultured cells, we found that the protein is distributed in intranuclear speckles, and unexpectedly also in intercellular junctions [6].
• Extension of these and other studies to mammalian systems required identification and cloning of the mammalian homologue of ash1 (the mammalian homologue of trx, ALL-1, was previously cloned) [6].
• Recently, we reported molecular studies indicating that TRX and ASH1 proteins act in concert to bind simultaneously to response elements located at close proximity within the same set of target genes [6].
• We have identified a human expressed sequence tag (EST) clone with similarity to the SET domain of Drosophila ASH1, and used it to clone the human gene. huASH1 resides at chromosomal band 1q21 [6].

Biological context of ASH1L

• Moreover, induction of HES-1 in a SCLC cell line down-regulates endogenous hASH1 gene expression [7].
• Although hASH1 probably plays a part in the growth and development of these tumors, its precise role and mechanism are unknown [3].
• The human gene, which we have termed human achaete-scute homology 1 (hASH1), was cloned from a human MTC cDNA library [8].
• Thus, hASH1 is a candidate locus for disease-causing mutations via triplet repeat amplification [8].
• Analysis of rodent-human somatic cell hybrids permitted assignment of hASH1 to human chromosome 12 [8].

Anatomical context of ASH1L

• Here, we show that Ash1 functions as a repressor that inhibits SWI/SNF binding and that Gcn5 is required to overcome Ash1 repression in mother cells to allow HO transcription [9].
• BACKGROUND: Human achaete-scute homolog-1 (hASH1), a fetal neural transcription factor, is highly expressed in neuroendocrine tumors such as medullary thyroid cancer (MTC) [3].
• Achaete-scute homolog-1 (termed Mash1 in rodents, hASH1 in humans) is a basic helix-loop-helix transcription factor important in early development of neural and neuroendocrine (NE) progenitor cells in multiple tissues including the CNS, autonomic nervous system, adrenal medulla, thyroid, lung, and prostate, among others [10].
• To explore the potential of ASH1 to promote NE differentiation and tumorigenesis in the lung, we constitutively expressed the factor in nonendocrine airway epithelial cells using transgenic mice [11].

Associations of ASH1L with chemical compounds

• METHODS: To determine the effect of raf-1 induction on hASH1 and hormone production, we used an estrogen inducible raf-1 construct in MTC cell line (TT) cells (TT-raf cells) [12].

Other interactions of ASH1L

• We conclude that: a) NeuroD1 is differentially expressed in PA and its possible ontogenetic and/or pathogenetic implications in non-corticotroph PA are discussed; b) ASH1 is a neuroendocrine marker whose expression is largely conserved in normal and neoplastic pituitary cells [2].

Analytical, diagnostic and therapeutic context of ASH1L

• Northern blots revealed hASH1 transcripts in RNA from a human MTC cell line, two fresh MTC tumors, fetal brain, and three lines of human SCLC [8].
• Binding of hASH-1 to the E-box cluster was confirmed by gel mobility-shift assay [13].

References