Disease relevance of Kras

• 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/ p21 signaling pathway: Implications for diabetic nephropathy [1].
• Structure of the c-Ki-ras gene in a rat fibrosarcoma induced by 1,8-dinitropyrene [2].
• Glucocorticoids stimulate p21 gene expression by targeting multiple transcriptional elements within a steroid responsive region of the p21waf1/cip1 promoter in rat hepatoma cells [3].
• Role of the increase in p21 in cisplatin-induced acute renal failure in rats [4].
• To further examine p21 regulation of the transitions between these cellular processes, an inducible p21 vector (lac operon system) was transfected into the rat pheochromocytoma (PC12) neural cell line [5].

High impact information on Kras

• Although p21, an inhibitor of cyclin-dependent kinase (Cdk) that is induced by DNA damage may partly account for the arrest in G1 (ref. 1), the mechanism is little understood [6].
• This bimolecular interaction provides a model for studying p21 regulation of mammalian phosphorylation signalling pathways [7].
• Using patch-clamp techniques, we find that agents activating PKC, including phorbol esters and a ras oncogene product (p21) that induces neurites, caused little increase in channel number [8].
• CONCLUSIONS: Polyamines negatively regulate junD gene expression posttranscriptionally, and increased JunD/AP-1 inhibits intestinal epithelial cell proliferation at least partially through the activation of p21 promoter [9].
• Ectopic expression of the wild-type junD increased p21-promoter activity and inhibited epithelial cell growth [9].

Chemical compound and disease context of Kras

• Finally, ectopic expression of p21 had no effect on hepatoma cell growth in the absence of glucocorticoids but facilitated the ability of dexamethasone to inhibit cell proliferation [3].
• When Cx43 was silenced by siRNA, neither tolbutamide nor dbcAMP were able to up-regulate p21 and consequently to reduce glioma cell proliferation, as judged by Ki-67 expression [10].
• Angiotensin-converting enzyme inhibitor preserves p21 and endothelial nitric oxide synthase expression in monocrotaline-induced pulmonary arterial hypertension in rats [11].
• The partially purified preparation contained a 22-kDa substrate for Clostridium botulinum C3 exoenzyme ADP-ribosyltransferase, which strongly reacted with anti-rhoA p21 antibody, but not with anti-rac1 p21 or anti-cdc42Hs p21 antibody [12].
• Although p21 of Harvey murine sarcoma virus-transformed NRK cells can be metabolically labeled with either [3H]palmitate or [3H]myristate, the lipid moiety of the hydrophobic peptide is identified as palmitic acid [13].

Biological context of Kras

• Characterization of c-Ki-ras oncogene alleles by direct sequencing of enzymatically amplified DNA from carcinogen-induced tumors [14].
• The hypothesis that fatty hepatocytes undergo cell cycle arrest due to (1) an inability to replenish ATP due to overexpressed uncoupling protein-2 (UCP-2) or (2) induction of growth inhibitor p21 leading to G1/S phase arrest was tested [15].
• The small GTPase p21 Ras and its downstream effectors play a central role in the control of cell survival and apoptosis [16].
• The sustained induction of p21 and p18 during myogenesis implicates these CDKI in maintaining cellular differentiation [17].
• Nucleotide sequence of exon I of the rat c-K-ras gene [18].

Anatomical context of Kras

• The period of maximal differentiation between days 9 to 13 was associated with a change in p21 and p16 staining from the external granular and Purkinje cells to a primarily Purkinje cell distribution [17].
• Next, rat balloon-injured carotid artery was analyzed for intimal thickening and p21 expression [19].
• Thus, the H-3/4 domain of HES-1 contributes to transcription repression independently of WRPW function, inhibits neurite formation, and facilitates two distinct and previously uncharacterized roles for HES-1: the inhibition of cell proliferation and the direct transcriptional repression of the NGF-induced gene, p21 [20].
• We consider a model in which the PC12 cell cycle is arrested as p21 accumulates and attains inhibitory levels relative to Cdk/cyclin complexes [21].
• The authors determined whether nontransformed rat intestinal epithelial cells (IECs) underwent reversible cell cycle arrest by contact inhibition, and determined whether increases in the relative amount of p21 associated with cyclin D/Cdk4 protein complexes were associated with cell growth arrest [22].

Associations of Kras with chemical compounds

• Simvastatin reversed the down-regulation of p21 protein expression and decreased CDK4 and CDK2 kinase activities [1].
• Nucleotide sequence analysis revealed that activated c-Ki-ras shows a G----T transversion in codon 12 and consequently encodes cysteine instead of glycine in normal rat c-Ki-ras [2].
• Immunohistochemical staining demonstrated that, in tranilast-treated rats, p21 was already present in the neointima at day 7 and strongly expressed throughout the neointima at day 14 [19].
• Analysis of 5' deletions of the p21 promoter uncovered a glucocorticoid responsive region between nucleotides -1481 and -1184, which does not contain a canonical glucocorticoid response element but which can confer dexamethasone responsiveness to a heterologous promoter [3].
• Initially, thymidine incorporation into DNA was dramatically inhibited; however, low levels of incorporation were observed during prolonged p21 expression [23].

Other interactions of Kras

• The CDKIs increased transiently during differentiation. p27 increased 20-fold between days 4 and 24, whereas p21 rose twofold between 6 to 11 days. p19, p18 and p16 increased approximately two- to threefold, falling to low levels in the adult [17].
• Further, during contact inhibition, there is more p21 associated with cyclin D1/Cdk4, which further contributes to the inhibition of the kinase complex [22].
• Recovery of Cdk4-dependent kinase activity occurred by 4 hours after release from growth arrest, coincident with decreased binding of p21 to the complex [22].
• Tolbutamide reduces glioma cell proliferation by increasing connexin43, which promotes the up-regulation of p21 and p27 and subsequent changes in retinoblastoma phosphorylation [10].
• The p27 complexed with Cdk2 dissociated after 2 days, whereas p21 associated in a reverse fashion [24].

Analytical, diagnostic and therapeutic context of Kras

• To confirm these findings, we applied a technique for direct sequence analysis of a 90-base-pair region of the rat c-Ki-ras gene produced by primer-directed enzymatic amplification [14].
• Immunofluorescence microscopy revealed that the overexpression of the dominant-negative RhoA led to a significant increase in p21 expression [1].
• Results from Western blots were consistent with phosphorylation of p21 protein coincident with the resumption of DNA synthesis [23].
• 2-acetaminofluorene blocks cell cycle progression after hepatectomy by p21 induction and lack of cyclin E expression [25].
• METHODS: Oxidative stress was induced in isolated rat pancreatic islet cells by treatment with H(2)O(2) and mRNA expression of p21 and insulin was examined by northern blot analyses [26].

References