Biomedical subjects

G F Claassen

Publications and source records attributed to G F Claassen.

3 recordsLinked to original sources

PubMed2000

A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor beta -induced cell-cycle arrest.

c-Myc plays a vital role in cell-cycle progression. Deregulated expression of c-Myc can overcome cell-cycle arrest in order to promote cellular proliferation. Transforming growth factor beta (TGFbeta) treatment of immortalized human keratinocyte cells inhibits cell-cycle progression and is characterized by down-regulation of c-Myc followed by up-regulation of p21(CIP1). A direct role of c-Myc in this pathway was demonstrated by the observation that ectopic expression of c-Myc overcame the cell-cycle block induced by TGFbeta treatment. The induction of p21(CIP1) transcription by TGFbeta was blocked in human keratinocyte cells stably expressing c-Myc. Furthermore, overexpression of c-Myc in NIH 3T3 cells repressed the basal levels of p21(CIP1) mRNA. Repression of p21(CIP1) transcription by c-Myc occurred at the promoter level in a region near the start site of transcriptional initiation and was independent of histone deacetylase activity. These data suggest that the down-regulation of c-Myc after TGFbeta signaling is important for subsequent regulation of p21(CIP1) and cell-cycle inhibition. Thus, repression of the cell-cycle inhibitory gene p21(CIP1) plays a role in c-Myc-dependent cell-cycle progression.

3T3 Cells↗

PubMed2000

The c-Myc transactivation domain is a direct modulator of apoptotic versus proliferative signals.

We have assayed the oncogenic, proliferative, and apoptotic activities of the frequent mutations that occur in the c-myc gene in Burkitt's lymphomas. Some alleles have a modest (50 to 60%) increase in transforming activity; however, the most frequent Burkitt's lymphoma allele (T58I) had an unexpected substantial decrease in transforming activity (85%). All alleles restored the proliferation function of c-Myc in cells that grow slowly due to a c-myc knockout. There was discordance for some alleles between apoptotic and oncogenic activities, but only the T58A allele had elevated transforming activity with a concomitant reduced apoptotic potential. We discovered a novel missense mutation, MycS71F, that had a very low apoptotic activity compared to wild-type Myc, yet this mutation has never been found in lymphomas, suggesting that there is no strong selection for antiapoptotic c-Myc alleles. MycS71F also induced very low levels of cytochrome c release from mitochondria, suggesting a mechanism of action for this mutation. Phosphopeptide mapping provided a biochemical basis for the dramatically different biological activities of the transformation-defective T58I and transformation-enhanced T58A c-Myc alleles. Furthermore, the antiapoptotic survival factor insulin-like growth factor 1 was found to suppress phosphorylation of T58, suggesting that the c-Myc transactivation domain is a direct target of survival signals.

Animals↗

PubMed1999

Myc-mediated transformation: the repression connection.

Myc is an important regulator of many cellular processes, including growth promotion, differentiation, and apoptosis. The mechanisms underlying Myc biological activity, however, remain elusive. For many years, research in the field has focused on the idea of Myc as a transactivator of gene expression. More recently, alternative mechanisms of Myc function have been proposed, including gene repression. In this review we present several lines of evidence to support a connection between Myc-mediated transformation and transcriptional repression.

Animals↗