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Effects of mutant Ran/TC4 proteins on cell cycle progression.

ABSTRACT: Ran/TC4, a member of the RAS gene superfamily, encodes an abundant nuclear protein that binds and hydrolyzes GTP. Transient expression of a Ran/TC4 mutant protein deficient in GTP hydrolysis blocked DNA replication, suggesting a role for Ran/TC4 in the regulation of cell cycle progression. To test this possibility, we exploited an efficient transfection system, involving the introduction of cDNAs in the pMT2 vector into 293/Tag cells, to analyze phenotypes associated with mutant and wild-type Ran/TC4 expression. Expression of a Ran/TC4 mutant protein deficient in GTP hydrolysis inhibited proliferation of transfected cells by arresting them predominantly in the G2, but also in the G1, phase of the cell cycle. Deletion of an acidic carboxy-terminal hexapeptide from the Ran/TC4 mutant did not alter its nuclear localization but did block its inhibitory effect on cell cycle progression. These data suggest that normal progression of the cell cycle is coupled to the operation of a Ran/TC4 GTPase cycle. Mediators of this coupling are likely to include the nuclear regulator of chromosome condensation 1 protein and the mitosis-promoting factor complex.

SUBMITTER: Ren M

PROVIDER: S-EPMC358787 | biostudies-other | 1994 Jun

REPOSITORIES: biostudies-other

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Effects of mutant Ran/TC4 proteins on cell cycle progression.

Ren M M Coutavas E E D'Eustachio P P Rush M G MG

Molecular and cellular biology 19940601 6

Ran/TC4, a member of the RAS gene superfamily, encodes an abundant nuclear protein that binds and hydrolyzes GTP. Transient expression of a Ran/TC4 mutant protein deficient in GTP hydrolysis blocked DNA replication, suggesting a role for Ran/TC4 in the regulation of cell cycle progression. To test this possibility, we exploited an efficient transfection system, involving the introduction of cDNAs in the pMT2 vector into 293/Tag cells, to analyze phenotypes associated with mutant and wild-type Ra ...[more]

PMID: 8196659

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Project description:Background:Activating mutations of the receptor tyrosine kinase KIT are early events in the development of most gastrointestinal stromal tumors (GISTs). Although GISTs generally remain dependent on oncogenic KIT during tumor progression, KIT mutations alone are insufficient to induce malignant behavior. This is evidenced by KIT-mutant micro-GISTs, which are present in up to one-third of normal individuals, but virtually never progress to malignancy. Methods:We performed whole exome sequencing on 29 tumors obtained from 21 patients with high grade or metastatic KIT-mutant GIST (discovery set). We further validated the frequency and potential prognostic significance of aberrations in CDKN2A/B, RB1, and TP53 in an independent series of 71 patients with primary GIST (validation set). Results:Using whole exome sequencing we found significant enrichment of genomic aberrations in cell cycle-associated genes (Fisher's Exact p = 0.001), most commonly affecting CDKN2A/B, RB1, and TP53 in our discovery set. We found a low mutational tumor burden in these 29 advanced GIST samples, a finding with significant implications for the development of immunotherapy for GIST. In addition, we found mutation of spliceosome genes in a minority of cases, implicating dysregulation of splicing as a potential cancer promoting mechanism in GIST. We next assessed the prognostic significance of CDKN2A, RB1 or TP53 mutation/copy loss in an independent cohort of 71 patients with primary GIST. Genetic events (mutation, deletion, and/or LOH) involving at least one of the three genes examined were found in 17% of the very low-risk, 36% of the low-risk, 42% of the intermediate risk, 67% of the high-risk/low mitotic-count, and in 86% of the high-risk/high mitotic-count group. The presence of cell cycle-related events was associated with a significantly shorter relapse-free survival (median 67 months versus not reached; p < 0.0001) and overall survival (Log Rank, p = 0.042). Conclusion:Our results demonstrate that genomic events targeting cell cycle-related genes are associated with GIST progression to malignant disease. Based on this data, we propose a model for molecular pathogenesis of malignant GIST.

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Effects of mutant Ran/TC4 proteins on cell cycle progression.

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Effects of mutant Ran/TC4 proteins on cell cycle progression.

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