Human homologue of maid: A dominant inhibitory helix-loop-helix protein associated with liver-specific gene expression

Abstract

The helix-loop-helix (HLH) family of transcriptional regulatory proteins are key regulators in numerous developmental processes. The class I HLH proteins, such as E12 are ubiquitously expressed. Class II HLH proteins, such as MyoD, are expressed in a tissue-specific manner. Class I and II heterodimers can bind to E-boxes (CANNTG) and regulate lineage commitments of embryonic cells. In an attempt to identify partners for the E12 protein that may exert control during liver development, we performed the yeast 2-hybrid screen using an expression complementary DNA library from human fetal liver. A novel dominant inhibitory HLH factor, designated HHM (human homologue of maid), was isolated and characterized. HHM is structurally related to the Id family and was highly expressed in brain, pituitary gland, lung, heart, placenta, fetal liver, and bone marrow. The helix-loop-helix (HLH) family of transcriptional regulation proteins are key regulators for various kinds of organ developmental processes. 1 Classification of the HLH proteins into 7 groups based on tissue distribution, dimerization capability, and DNA-binding specificities has been devised. 2 Briefly, class I HLH proteins, such as E12, E47, HEB, E2-2, and Daughterless, are also called E proteins. These proteins are ubiquitously expressed in many tissues and make either homodimers or heterodimers. 3 The specific DNA-binding site of class I proteins is known as an E-box, having the consensus sequence CANNTG. 4 Class II HLH proteins, such as MyoD, myogenin, Atonal, and NeuroD/BETA2, show a tissue-specific expression pattern. [5][6][7][8][9][10][11][12] With few exceptions, they are incapable of forming homodimers and preferentially heterodimerize with the E proteins. The heterodimer of class I and II HLH proteins bind to the E-boxes that are found in a number of cell type-specific promoters and enhancers and regulate different developmental pathways, such as myogenesis, neurogenesis, lymphopoiesis, and sex determination. [13][14][15] Class III HLH proteins include the Myc family of transcription factors, TFE3, SREBP-1, and the Microphthalmia-associated transcription factor, Mi. Proteins of this class contain a leucine zipper (LZ) adjacent with the HLH motif. 16,17 Class IV HLH proteins included Mad, Max, and Mxi, that are capable of dimerizing with the Myc proteins or with one another. [18][19][20] Class V HLH proteins lack the basic domain and consequently do not bind to DNA. These include Id and emc. [21][22][23][24][25][26] Class VI HLH proteins have a specific feature that includes a proline in their basic region. Drosophila proteins Hairy and Enhancer of split are included in this class. 27,28 The class VII HLH proteins are characterized by the presence of the bHLH-PAS domain and include the aromatic hydrocarbon receptor and its nucleartranslocator. 29 It has been clearly shown that the basic HLH (bHLH) factor can directly or indirectly regulate a network of gene expressions. 1 This regulation can be either "enabling," i.e., promoting an execution of a differ...

Ribosomal phosphoprotein P0 interacts with GCIP and overexpression of P0 is associated with cellular proliferation in breast and liver carcinoma cells

“…This study presents results that demonstrate a physical interaction between P0 and a novel protein, GCIP, a human Grap2 and Cyclin D Interacting Protein (Xia et al, 2000), which is also recognized as a human homolog of MAID protein (HHM) (Terai et al, 2000) and a D-type cyclininteracting protein 1 (DIP1) (Yao et al, 2000). We further show here that increased expression of P0 in cells could execute its oncogenic activity by inhibiting GCIPmediated reduction of Rb phosphorylation and enhance the expression of cyclin D1.…”

Expression of GCIP in transgenic mice decreases susceptibility to chemical hepatocarcinogenesis

“…and differentiation (Xia et al, 2000). Previous data from Thorgeirsson's group had shown that GCIP/HHM is expressed specifically in the foci of the 2-acetylaminofluorene/partial hepatectomy (AAF/PH) model and is likely to be involved in hepatic stem cell (hepatic oval cell) proliferation and differentiation (Terai et al, 2000). GCIP/HHM was also demonstrated to regulate the transcriptional activation of hepatocyte nuclear factor 4 (HNF4) in reporter assays, suggesting a role of GCIP/ HHM in liver growth and differentiation (Terai et al, 2000).…”

“…GCIP (CCNDBP1) is a HLH leucine zipper (HLH-LZ) proteins without basic DNA-binding region, which was identified and characterized in our lab and others to interact with cyclinD1 (DIP1) and as a human homologue of MAID protein (HHM) (Hwang et al, 1997;Terai et al, 2000;Xia et al, 2000;Yao et al, 2000). GCIP gene is localized on chromosome 15q15, a region frequently deleted or undergoes loss of heterozygosity (LOH) in different tumors, including colorectum, breast, lung, and bladder tumor (Natrajan et al, 2003).…”

“…GCIP gene is localized on chromosome 15q15, a region frequently deleted or undergoes loss of heterozygosity (LOH) in different tumors, including colorectum, breast, lung, and bladder tumor (Natrajan et al, 2003). Previous data demonstrate that GCIP is expressed specifically in foci of the 2-acetylaminofluorene/ partial hepatectomy (AAF/PH) model, which is used to monitor the differentiation of rat hepatic stem cells into hepatocytes, suggesting GCIP may be involved in the hepatic stem cell development and differentiation processes (Terai et al, 2000). GCIP was also showed to regulate the transcription of hepatocyte nuclear factor 4 (HNF4), which has E-box sequences in its promoters, thus suggesting that GCIP might be involved in the liver growth and differentiation (Terai et al, 2000;Takami et al, 2005).…”

“…Previous data demonstrate that GCIP is expressed specifically in foci of the 2-acetylaminofluorene/ partial hepatectomy (AAF/PH) model, which is used to monitor the differentiation of rat hepatic stem cells into hepatocytes, suggesting GCIP may be involved in the hepatic stem cell development and differentiation processes (Terai et al, 2000). GCIP was also showed to regulate the transcription of hepatocyte nuclear factor 4 (HNF4), which has E-box sequences in its promoters, thus suggesting that GCIP might be involved in the liver growth and differentiation (Terai et al, 2000;Takami et al, 2005). High-level expression of GCIP was found from the very early stages of hepatocarcinogenesis, suggesting that GCIP might be involved in hepatocarcinogenesis (Takami et al, 2005).…”