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Overview

INSM1 (formerly IA-1) functions as a zinc-finger transcriptional repressor originally cloned from a human insulinoma subtraction library[1]. INSM1 protein is highly conserved in homologues of different species including Drosophila, zebrafish, medeka, Xenopus, and C. elegans[2]. The INSM1 mRNA pattern of expression in normal tissues is restricted to developing neuroendocrine and embryonic nervous systems[3](Figure 1). In pancreatic endocrine cell development, Ngn3, INSM1, and NeuroD/beta2 form a tight transcriptional network that is essential for beta cell development[4](Figure 2). Furthermore, global deletion of INSM1 has shown its crucial role in the differentiation of the endocrine pancreas, intestinal endocrine cells, sympatho-adrenal lineage, the basal progenitors of the neocortex, and the hindbrain monoaminergic neurons that include both the serotonergic and noradrenergic subtypes. INSM1 deletion severely impairs catecholamine biosynthesis and secretion from the adrenal gland that results in early embryonic lethality[5]. During sympatho-adrenal lineage formation, INSM1 acts as a downstream factor of Mash1 and Phox2b. In the developing neocortex, INSM1 contributes to the maintenance of the number of basal progenitors and to cortical plate radial development[6]. INSM1 is expressed in the hindbrain monoaminergic neurons and is crucial for the differentiation of the serotonergic and noradrenergic subtypes. The proneural factor Ascl1 (Mash1) binds to a cis-regulatory element in the INSM1 sequence and is esential for INSM1 expression in the ventral hindbrain. [7] INSM1 functions as a transcriptional repressor to directly regulate NeuroD/beta2, insulin, and INSM1 itself as target genes, but also interacts with cyclin D1[8]. Cyclin D1 and INSM1 when bound to the NeuroD1 and insulin gene promoters form a complex with the the co-repressor HDAC-1 and HDAC-3. [9] Additionally, the interaction between INSM1 and cyclin D1 directly interferes with cyclin D1/CDK4 binding and induces cell cycle arrest/exit necessary to facilitate cellular differentiation (Figure 3). Direct evidence supports that INSM1 functions as a transient differentiation factor that controls the early stages of neuroendocrine cell differentiation. The functional effect of INSM1 on pancreatic cells was reported as over-expression of INSM1 could modulate multiple islet transcription factors and promote pancreatic cell trans-differentiation [10][11].

INSM1 is expressed predominantly in neuroendocrine tumors including insulinoma, small cell lung carcinoma, pituitary tumor, pheochromacytoma, medullary thyroid carcinoma, medulloblastoma, neuroblastoma, and retinoblastoma[1]. The INSM1 promoter confers tissue-restricted expression and therefore the neuroendocrine-specific promoter could drive targeted cancer gene therapy for the treatment of neuroendocrine tumors[12][13].

References
  1. Goto Y et al. A novel human insulinoma-associated cDNA, IA-1, encodes a protein with "zinc-finger" DNA-binding motifs. J. Biol. Chem., 267(21):15252-7. (PMID 1634555)
  2. Xie J et al. The zinc-finger transcription factor INSM1 is expressed during embryo development and interacts with the Cbl-associated protein. Genomics, 80(1):54-61. (PMID 12079283)
  3. Lan MS and Breslin MB. Structure, expression, and biological function of INSM1 transcription factor in neuroendocrine differentiation. FASEB J., 23(7):2024-33. (PMID 19246490)
  4. Gierl MS et al. The zinc-finger factor Insm1 (IA-1) is essential for the development of pancreatic beta cells and intestinal endocrine cells. Genes Dev., 20(17):2465-78. (PMID 16951258)
  5. Wildner H et al. Insm1 (IA-1) is a crucial component of the transcriptional network that controls differentiation of the sympatho-adrenal lineage. Development, 135(3):473-81. (PMID 18094025)
  6. Farkas LM et al. Insulinoma-associated 1 has a panneurogenic role and promotes the generation and expansion of basal progenitors in the developing mouse neocortex. Neuron, 60(1):40-55. (PMID 18940587)
  7. Jacob J et al. Insm1 (IA-1) is an essential component of the regulatory network that specifies monoaminergic neuronal phenotypes in the vertebrate hindbrain. Development, 136(14):2477-85. (PMID 19542360)
  1. Zhang T et al. Zinc Finger Transcription Factor INSM1 Interrupts Cyclin D1 and CDK4 Binding and Induces Cell Cycle Arrest. J. Biol. Chem., 284(9):5574-81. (PMID 19124461)
  2. Liu WD et al. INSM1 functions as a transcriptional repressor of the neuroD/beta2 gene through the recruitment of cyclin D1 and histone deacetylases. Biochem. J., 397(1):169-77. (PMID 16569215)
  3. Zhang T et al. Insulinoma-associated antigen-1 zinc-finger transcription factor promotes pancreatic duct cell trans-differentiation. Endocrinology, 151(5):2030-9. (PMID 20215568)
  4. Zhang T et al. Functional role of an islet transcription factor, INSM1/IA-1, on pancreatic acinar cell trans-differentiation. J. Cell. Physiol., 227(6):2470-9. (PMID 21830214)
  5. Wang HW et al. INSM1-promoter driven adenoviral HSV thymidine kinase cancer gene therapy for the treatment of primitive neuroectodermal tumors. Hum. Gene Ther. (PMID 19604042)
  6. Pedersen N et al. The insulinoma-associated 1: a novel promoter for targeted cancer gene therapy for small-cell lung cancer. Cancer Gene Ther., 13(4):375-84. (PMID 16052225)
Figures
FIGURE 1 INSM1/IA-1 expression patterns.
A collection of cell lines and tissues were tested for INSM1 gene expression by Northern blot analysis and RT-PCR. Most of the tumors of neuroendocrine origin highly express INSM1 gene. Embryonic neuroendocrine tissues also express INSM1 indicating that INSM1 could be a differentiation factor in neuroendocrine differentiation.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.