Disease relevance of ASCL1

• Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma [1].
• Quantitative reverse transcription-polymerase chain reaction measurement of HASH1 (ASCL1), a marker for small cell lung carcinomas with neuroendocrine features [2].
• Genetic association analyses of PHOX2B and ASCL1 in neuropsychiatric disorders: evidence for association of ASCL1 with Parkinson's disease [3].
• Furthermore, E2-2 seems to be one of the major HASH-1 interacting proteins in extracts from neuroblastoma cells [4].
• This review discusses how progress in developmental neurobiology of Mash1 has translated into novel insights in NE tumor biology, particularly for small cell lung cancer [5].

Psychiatry related information on ASCL1

• The transition from proliferation to neurogenesis involves a coordinate increase in the activity of proneural bHLH factors (Mash1, Neurogenin1, and Neurogenin2) and a decrease in the activity of Hes and Id factors [6].
• As Mash and Hunsley (2005) discuss in this special section, evidence-based assessment tools not only demonstrate adequate psychometric qualities, but also have relevance to the delivery of services to individuals with the disorder (see also Hayes, Nelson, & Jarrett, 1987) [7].
• Examined the convergent and discriminant validity of the Parent Attribution Test (PAT; Bugental, Blue, & Cruzcosa, 1989), the Parental Locus of Control Scale (PLOC; Campis, Lyman, & Prentice-Dunn, 1986), and the Parenting Sense of Competence-Efficacy Scale (PSOC-Efficacy; Johnston & Mash, 1989) in 3 samples of community mothers [8].

High impact information on ASCL1

• The second lineage, characterized by the expression of Dlx1/2 but not Mash1, forms around 35% of the GABAergic neurons and originates from the ganglionic eminence of the ventral forebrain [9].
• What are the roles of MASH1 and other regulatory genes in controlling early stages in neural crest cell determination, and how is the expression of these molecules in turn controlled [10]?
• Using this approach, we demonstrate that Mash1 has the capacity to respecify the identity of neuronal populations normally derived from Ngn2-expressing progenitors in the dorsal telencephalon and ventral spinal cord [11].
• Thus, Hes5-dependent modulation of myelin gene expression involves old players (i.e. Mash1) and novel mechanisms of transcriptional regulation that include cell-specific regulatory loops with transcriptional activators (i.e. Sox10) [12].
• Conservation of the Drosophila lateral inhibition pathway in human lung cancer: a hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression [13].

Biological context of ASCL1

• The genetic contributions of PHOX2B and ASCL1 were examined separately, along with epistatic interactions with broader candidate phenotypes [3].
• We also localized ASCL1 in the 12q22-q23 cytogenetic interval by using fluorescence in situ hybridization [14].
• ASCL1, the human achaete-scute homolog, is a helix-loop-helix transcription factor that was previously assigned to chromosome 12 using a rodent-human somatic hybrid panel [14].
• We have previously shown that HASH-1 is expressed in neuroblastoma tumors and cell lines, and in this study we have used the yeast two-hybrid system to isolate HASH-1 interacting proteins from a human neuroblastoma cDNA library [4].
• One important negative regulator of MASH-1 expression is the bHLH factor hairy and Enhancer of split homolog-1 (HES-1), which in turn is under positive control of the Notch signaling cascade [15].

Anatomical context of ASCL1

• As ASCL has been implicated in neuroendocrine, medullary thyroid and small-cell lung cancers, we chose to examine the role of ASCL1 in the astrocytoma development [1].
• ASCL1 controls development of the locus coeruleus (LC), and accumulating evidence suggests that the LC confers protective effects against the dopaminergic neurodegeneration inherent in PD [3].
• In conclusion, E2-2 forms a functional complex with HASH-1, and might therefore be involved in the development of specific parts of the central and peripheral nervous systems [4].
• 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 [5].
• To analyze the functional consequences of HASH-1 mutations, we developed an in vitro model of noradrenergic differentiation in neuronal progenitors derived from the mouse vagal neural crest, reproducing in vitro the HASH-PHOX-RET pathway [16].

Associations of ASCL1 with chemical compounds

• The present genetic data may thus suggest that polyglutamine length polymorphisms in ASCL1 could influence predispositions to PD through the fine-tuning of LC integrity [3].
• Treatment of TT-NOTCH cells with doxycycline led to dose-dependent induction of NOTCH1 protein with corresponding decreases in ASCL1 protein and NE hormones [17].
• Further, TT cells were treated with nontoxic concentrations of LY294002 for 2 days, and Western blot analyses were performed for phospho-Akt, total Akt, and the NE tumor markers CgA and human achaete-scute homolog1 (ASCL1) [18].
• Differential actions of the proneural genes encoding Mash1 and neurogenins in Nurr1-induced dopamine neuron differentiation [19].
• Furthermore, a demethylating agent, 5-aza-2'-deoxycytidine, reactivated the ASCL expression in the methylation-silenced cells, indicating that ASCL is silenced by the associated DNA methylation [20].

Physical interactions of ASCL1

• The HASH-1/E2-2 complex binds an E-box (CACCTG) in vitro, and transactivates an E-box containing reporter construct in vivo [4].

Regulatory relationships of ASCL1

• Conversely, null mutation of HES1 up-regulates Mash1 expression, accelerates neuronal differentiation, and causes severe defects of the brain and eyes [21].
• The expression of HASH-1 was also up-regulated by IFN-gamma [22].
• Conversely, Mash1 induces neuronal differentiation characterized by the expression of generic neuronal genes SCG10, Hu and NF160; however, only a subpopulation of these neurons also displays an autonomic, noradrenergic phenotype [23].

Other interactions of ASCL1

• The deletion of the PAH, IGF1, and ASCL1 genes could explain the patient's phenotype corresponding to a contiguous gene syndrome [24].
• Logistic regression analysis revealed the effect of ASCL1 dominant x PHOX2B additive (P=0.008) as an epistatic gene-gene interaction increasing risk of PD [3].
• When neuroblastoma cells are induced to differentiate, as indicated by neuronal morphology and upregulation of neuronal marker genes, the HASH-1 expression is rapidly downregulated with a concomitant, transient upregulation of HES-1 [15].
• Prolactin and ACTH tumors had the highest levels of expression of hASH-1 [25].
• Domain-swapping experiments with Mash1 and NeuroD indicated that the helix-loop-helix domain, responsible for mediating dimerization of bHLH transcription factors, imparts the distinct effect [19].

Analytical, diagnostic and therapeutic context of ASCL1

• By real-time RT-PCR, the amounts of hASH1 mRNA in a small cell NEC were 16,600 times higher than those in adenocarcinomas and 110 times higher than those in a carcinoid tumor [26].
• Dual promoters initiate hASH1 transcription, with the predominant site being an evolutionarily conserved initiator (INR) element [27].
• On transplantation into the striatum of Parkinsonian rats, precursor cells engineered with Nurr1/SHH/Bcl-XL or Nurr1/Mash1 survived in vivo and differentiated into mature DA neurons that can reverse the behavioral deficits in the grafted animals [28].
• Furthermore, manipulation of the BMP signaling pathway in vivo via electroporation of expression vectors encoding either BMP or NOGGIN coupled with MASH1 gain-of-function experiments demonstrate that a BMP-mediated transcriptional cascade involving Cash1 and Tlx-3 specifies first-order relay sensory neurons in the developing brainstem [29].
• Sequence alignment of the predicted amino acid sequence of Fash1 with other vertebrate homologs of the achaete scute homolog 1 subclass shows that the carboxyl 2/3 of the protein, including the basic helix-loop-helix, a putative nuclear localization signal and several consensus phosphorylation sites, is highly conserved [30].

References