Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10412 (H1.4)
 75 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Global histone H1 phosphorylation correlates with cell cycle progression. However, the function of site-specific H1 variant phosphorylation remains unclear. Our mass spectrometry analysis revealed a novel N-terminal phosphorylation of the major H1 variant H1.4 at serine 35 (H1.4S35ph), which accumulates at mitosis immediately after H3 phosphorylation at serine 10. Protein kinase A (PKA) was found to be a kinase for H1.4S35. Importantly, Ser-35-phosphorylated H1.4 dissociates from mitotic chromatin. Moreover, H1.4S35A substitution mutant cannot efficiently rescue the mitotic defect following H1.4 depletion, and inhibition of PKA activity increases the mitotic chromatin compaction depending on H1.4. Our results not only indicate that PKA-mediated H1.4S35 phosphorylation dissociates H1.4 from mitotic chromatin but also suggest that this phosphorylation is necessary for specific mitotic functions.
 ...
PMID:Protein kinase A-mediated serine 35 phosphorylation dissociates histone H1.4 from mitotic chromosome. 2185 32

Background: Osteosarcoma is prevalent in children and adolescents. H1.4 modification is involved in various types of cancers. Ras pathway is often activated in human cancers. Herein, we explored the effects of Ras pathway through H1.4S35ph. Methods: Osteosarcoma cancer cell line MG-63 was transfected with Ras gene with G12V and Y40C site mutation. The phosphorylation of H1.4S35 and AKT was detected by Western blot. Cell viability, cell colonies and migration were analyzed by MTT assay, soft-agar colony formation assay and Transwell assay, respectively. The expression of Ras pathway downstream factors and PKA was detected by qRT-PCR. The relationship between Ras and downstream factors was detected by ChIP. The cell cycle progression was measured by flow cytometry. Results: Transfection with RasG12V/Y40C decreased H1.4S35ph expression while switched on p-AKTSer473. RasG12V/Y40C increased cell viability, colony numbers and migration while H1.4S35E (H1.4S35ph overexpression) led to the opposite results. The regulation of RasG12V/Y40C and H1.4S35E on Ras downstream factors was contrary to each other. Results demonstrated a positive relationship between PKA with H1.4S35ph with RasG12V/Y40C down-regulated both. However, PKA and MDM2 revealed negative regulation with RasG12V/Y40C transfection up-regulated MDM2. Conclusion: RasG12V/Y40C-PI3K/AKT signal pathway decreased H1.4S35ph through down-regulation of PKA while up-regulation of MDM2 in MG-63 cells. Highlights H1.4S35ph is regulated by K-RasG12V/Y40-PI3K/AKT in MG-63 cells; Overexpression of H1.4S35ph regulates MG-63 cell growth; H1.4S35ph regulates Ras downstream factors; K-RasG12V/Y40C-PI3K/AKT activity induces PKA degradation to down-regulate H1.4S35ph; K-RasG12V/Y40C-PI3K/AKT activity involves in PKA degradation via MDM2.
 ...
PMID:K-RasG12V/Y40C-PI3K/AKT pathway regulates H1.4S35ph through PKA to promote the occurrence and development of osteosarcoma cancer. 3244 Nov 46

Recent papers suggest that oncogenic Ras participate in regulating tumour cells proliferation and metastasis. This work linked Ras with H1.4 modification in non-small-cell lung carcinoma (NSCLC), to better understand the oncogenic effects of Ras. A plasmid for expressing Ras mutated at G13D and T35S was transfected into NCI-H2126 and A549 cells. Phosphorylation of H1.4S36 was determined by immunoblotting. Effects of phosphorylation of H1.4 at serine (S) 36 (H1.4S36ph) on NCI-H2126 and A549 cells were tested by MTT assay, soft-agar colony formation assay, flow cytometry and transwell assay. Chromatin-immunoprecipitation (ChIP) and RT-qPCR were conducted to measure the effects of H1.4S36ph on Ras downstream genes. The catalyzing enzymes participate in H1.4S36 phosphorylation were further studied. We found that Ras-ERK signalling repressed the phosphorylation of H1.4 at S36. H1.4S36ph functioned as a tumour suppressor, as its overexpression repressed NCI-H2126 and A549 cells viability, colony formation, S-phase arrest, migration and invasion. H1.4S36ph was able to mediate the transcription of Ras downstream genes. Ras-ERK signalling repressed H1.4S36ph through degradation of PKA, and the degradation was mediated by MDM2. In conclusion, Ras-ERK signalling repressed H1.4 phosphorylation at S36 to participate in NSCLC cells growth, migration and invasion. Ras-ERK signalling repressed H1.4S36ph through MDM2-dependent degradation of PKA. This study provides a novel explanation for Ras-ERK's tumour-promoting function. Highlights: H1.4S36 phosphorylation is repressed by Ras-ERK activation; H1.4S36ph inhibits the phenotype of NSCLC cells; H1.4S36ph regulates the transcription of Ras downstream genes; Ras-ERK represses H1.4S36ph by MDM2-dependent degradation of PKA.
 ...
PMID:Ras-ERK signalling represses H1.4 phosphorylation at serine 36 to promote non-small-cell lung carcinoma cells growth and migration. 3118 27