Disease relevance of CCNH

• Cell lines with gain on proximal 5q, where CCNB1 and CCNH reside, showed an increased growth rate, suggesting that cyclins activating cdc2, the dominant G2/M phase kinase, may play a role in glioma tumorigenes [1].
• Expression in Escherichia coli: purification and characterization of cyclin H, a subunit of the human general transcription/DNA repair factor TFIIH [2].
• p35 and p37 are Borrelia burgdorferi genes encoding 35 and 37 kDa proteins [3].
• OBJECTIVE: To study the role of cell cycle regulation during HIV infection by investigating in vivo and in vitro cyclin B and p34 cdc kinase expression [4].
• These data show that ospA is repressed while p35 and p37 are induced in human infection; these results are the first direct demonstration of differential B. burgdorferi gene expression during Lyme disease [5].

High impact information on CCNH

• In addition, mimicking cdk8 phosphorylation of cyclin H in vivo has a dominant-negative effect on cell growth [6].
• Here we use a yeast two-hybrid screen to show that a new human cyclin (cyclin H) is a MO15-associated protein [7].
• Recent results on the structures of two cyclins, cyclin A and cyclin H, and two transcription factor mediator proteins, TFIIB and the A pocket region of the retinoblastoma tumour suppressor protein (Rb), show that they share domains with a strikingly similar alpha-helical topology, despite remote sequence identity [8].
• The subunits of this enzyme have been identified recently as p40MO15, the catalytic subunit, and cyclin H, a regulatory subunit [9].
• The specificity of the cyclin H molecule is provided mainly by two long helices which extend the cyclin fold at its N- and C-termini and pack together against the first repeat on the side opposite to the kinase [10].

Chemical compound and disease context of CCNH

• FTY720 eliminated proliferating cell nuclear antigen, retinoblastoma family members, differentiation regulated transcription factor polypetide-1, and cyclin H. These cell-cycle regulators were not eliminated when the peptide inhibitor was used [11].

Biological context of CCNH

• We show that Crk1 associates with the Mcs2 mitotic catastrophe suppressor, a cyclin H-like molecule, and overexpression of crk1 rescues the cell-cycle arrest defect of a mcs2-75 cdc2-3w cdc25-22 triple mutant at high temperature [12].
• This is the first report showing that cyclin H-mediated down-regulation of cdk-activating kinase activity is involved in growth arrest induced by lack of anchorage [13].
• It is proposed that the CDK7-cyclin H complex functions in cell cycle progression, basal transcription and DNA repair [14].
• Here, we show that phosphorylation of S77 governing the transcriptional activity of RARalpha depends on cyclin H binding at a RARalpha region that encompasses loop 8-9 and the N-terminal tip of helix 9 of the AF-2 domain [15].
• A kinase responsible for this specific phosphorylation, called CAK for cdk-activating kinase, has been recently purified from starfish and Xenopus oocytes and shown to contain the MO15 gene product as a catalytic subunit [16].

Anatomical context of CCNH

• The human MAT1 gene expresses a single 1.6-kb transcript, the steady-state level of which, like CDK7 and cyclin H, varies significantly in different cell lines and in different terminally differentiated tissues [17].
• Finally, both cyclin H and cdk7 did not colocalize with P80 coilin after disruption of the coiled body, indicating that these proteins are specifically targeted to the small nuclear ribonucleoprotein-containing domain [18].
• The nuclear localization of both the MO15 gene product and CAK activity may imply that cdks activation primarily occurs in the cell nucleus [16].
• However, in peripheral blood lymphocytes (PBL) from HIV-infected patients, cyclin B and p34 cdc kinase show premature expression during the cell cycle [4].
• Unscheduled cyclin B expression and p34 cdc2 activation in T lymphocytes from HIV-infected patients [4].

Associations of CCNH with chemical compounds

• Full activation of CDK7 requires association with a positive regulatory subunit, cyclin H, and phosphorylation of a conserved threonine residue at position 170 in its own T loop [19].
• Phosphorylation by PKA potentiates retinoic acid receptor alpha activity by means of increasing interaction with and phosphorylation by cyclin H/cdk7 [20].
• Sucrose density gradient ultracentrifugation of a mixture of 125I-PAP p37 and IgG also revealed the fluid-phase complex formation with a sedimentation value of 19S [21].
• The cell-surface glycoprotein CD36 interacts with a large variety of ligands, including collagen types I and IV, thrombospondin, erythrocytes parasitized with Plasmodium falciparum, platelet-agglutinating protein p37, oxidized low density lipoprotein, and long-chain fatty acids [22].
• The binding of arachidonic acid is saturable with a single class of binding site per FA-p34, and a dissociation constant (Kd) of 0.13 microM is calculated [23].

Physical interactions of CCNH

• Little is known about the regulation of the CAK complex through cyclin H. In this study we further analyzed cyclin H regulation and identified two basic clusters in the C terminus of the protein as putative nuclear localization sequences (NLSs) [24].
• In vitro assembly of a functional human CDK7-cyclin H complex requires MAT1, a novel 36 kDa RING finger protein [14].
• Lymphocytes isolated from human immunodeficiency virus (HIV)-infected patients have dysregulated cell-cycle control, consisting of increased activation of the cyclin B1/p34 cdc2 complex and abnormal nucleolar structure [25].
• Cell cycle progression in eukaryotes is controlled by complexes of p34 protein kinases and cyclins [26].
• Taken together, MCT-1 is a novel candidate oncogene with homology to a protein-protein binding domain of cyclin H [27].

Other interactions of CCNH

• Also, Mop1 and Mcs2 can associate with the heterologous partners human cyclin H and MO15, respectively [28].
• This suggests that Mop1 would be a CDK, and indeed Mop1 associates with a previously characterized cyclin H-related cyclin Mcs2 of S.pombe [28].
• p53 is phosphorylated by CDK7-cyclin H in a p36MAT1-dependent manner [29].
• The kinase is composed of three subunits: CDK7, Cyclin H and MAT1 (ménage a trois) [30].
• The human cyclin H, a protein normally associated with the cyclin-dependent kinase cdk7, was overexpressed in Escherichia coli using a T7 RNA polymerase expression system and further purified to apparent homogeneity [2].

Analytical, diagnostic and therapeutic context of CCNH

• Immunofluorescence analysis showed that cyclin H and CK2alpha were colocated in the nucleus [31].
• Far Western blot experiments revealed that cyclin H bound to the alpha-subunit but not the alpha(')- and beta-subunits of CK2 [31].
• Hierarchical clustering of nuclear gene expression, examined at p37 by the NCI cDNA microarray in AZT-exposed cells, showed down-regulation of 13 out of 16 lipid-metabolizing genes, and up-regulation of most oxidative phosphorylation (OXPHOS) genes [32].
• Confocal microscopy revealed the co-localization of PKC-iota with CAK/cdk7 in both the cytoplasm and nucleus of U-373 MG cells [33].
• In vitro phosphorylation, co-immunoprecipitation, and analysis of phosphorylated proteins by autoradiography indicate that CAK (cdk7) is a substrate for PKC-iota and PKC-betaII hyperphosphorylation [34].

References