Biomedical subjects

Marie Classon

Publications and source records attributed to Marie Classon.

6 recordsLinked to original sources

PubMed2006

A common signaling cascade may underlie "addiction" to the Src, BCR-ABL, and EGF receptor oncogenes.

"Oncogene addiction" describes an unexplained dependency of cancer cells on a particular cellular pathway for survival or proliferation. We report that differential attenuation rates of prosurvival and proapoptotic signals in oncogene-dependent cells contribute to cell death following oncogene inactivation. Src-, BCR-ABL-, and EGF receptor-dependent cells exhibit a similar profile of signal attenuation following oncogene inactivation characterized by rapid diminution of phospho-ERK, -Akt, and -STAT3/5, and a delayed accumulation of the proapoptotic effector phospho-p38 MAPK. These findings implicate a transient imbalance in survival and apoptotic oncogenic outputs in the apoptotic response to oncogene inactivation. Moreover, these observations implicate a common profile of signal attenuation for multiple oncogenes and suggest that "addiction" associated with apoptosis reflects an active rather than a passive process.

Animals↗

PubMed2006

The retinoblastoma protein is required for Ras-induced oncogenic transformation.

Most human cancers involve either mutational activation of the Ras oncogenic pathway and/or inactivation of the retinoblastoma tumor suppressor (RB) pathway. Paradoxically, tumors that harbor Ras mutations almost invariably retain expression of a wild-type pRB protein. We explain this phenomenon by demonstrating that Ras-induced oncogenic transformation surprisingly depends on functional pRB protein. Cells lacking pRB are less susceptible to the oncogenic actions of H-RasV12 than wild-type cells and activated Ras has an inhibitory effect on the proliferation of pRB-deficient human tumor cells. In addition, depletion of pRB from Ras-transformed murine cells or human tumor cells that harbor Ras pathway mutations inhibits their proliferation and anchorage-independent growth. In sharp contrast to pRB-/- 3T3 cells, fibroblasts deficient in other pRB family members (p107 and p130) are more susceptible to Ras-mediated transformation than wild-type 3T3 cells. Moreover, loss of pRB in tumor cells harboring a Ras mutation results in increased expression of p107, and overexpression of p107 but not pRB strongly inhibits proliferation of these tumor cells. Together, these findings suggest that pRB and p107 have distinct roles in Ras-mediated transformation and suggest a novel tumor-suppressive role for p107 in the context of activated Ras.

3T3 Cells↗

PubMed2005

Notch1 modulates timing of G1-S progression by inducing SKP2 transcription and p27 Kip1 degradation.

Cyclin-dependent kinase inhibitors (CKIs) and Notch receptor activation have been shown to influence adult stem cells and progenitors by altering stem cell self-renewal and proliferation. Yet, no interaction between these molecular pathways has been defined. Here we show that ligand-independent and ligand-dependent activation of Notch1 induces transcription of the S phase kinase-associated protein 2 (SKP2), the F-box subunit of the ubiquitin-ligase complex SCF(SKP2) that targets proteins for degradation. Up-regulation of SKP2 by Notch signaling enhances proteasome-mediated degradation of the CKIs, p27 Kip1 and p21 Cip1, and causes premature entry into S phase. Silencing of SKP2 by RNA interference in G1 stabilizes p27 Kip1 and p21 Cip1 and abolishes Notch effect on G1-S progression. Thus, SKP2 serves to link Notch1 activation with the cell cycle machinery. This novel pathway involving Notch/SKP2/CKIs connects a cell surface receptor with proximate mediators of cell cycle activity, and suggests a mechanism by which a known physiologic mediator of cell fate determination interfaces with cell cycle control.

3T3 Cells↗

PubMed2003

NPAT expression is regulated by E2F and is essential for cell cycle progression.

NPAT is an in vivo substrate of cyclin E-Cdk2 kinase and is thought to play a critical role in coordinated transcriptional activation of histone genes during the G(1)/S-phase transition and in S-phase entry in mammalian cells. Here we show that NPAT transcription is up-regulated at the G(1)/S-phase boundary in growth-stimulated cells and that the NPAT promoter responds to activation by E2F proteins. We demonstrate that endogenous E2F proteins interact with the promoter of the NPAT gene in vivo and that induced expression of E2F1 stimulates NPAT mRNA expression, supporting the idea that the expression of NPAT is regulated by E2F. Consistently, we find that the E2F sites in the NPAT promoter are required for its activation during the G(1)/S-phase transition. Moreover, we show that the expression of NPAT accelerates S-phase entry in cells released from quiescence. The inhibition of NPAT expression by small interfering RNA duplexes impedes cell cycle progression and histone gene expression in tissue culture cells. Thus, NPAT is an important E2F target that is required for cell cycle progression in mammalian cells. As NPAT is involved in the regulation of S-phase-specific histone gene transcription, our findings indicate that NPAT links E2F to the activation of S-phase-specific histone gene transcription.

3T3 Cells↗

PubMed2002

Modulation of CREB activity by the Rho GTPase regulates cell and organism size during mouse embryonic development.

Rho GTPases regulate several aspects of tissue morphogenesis during animal development. We found that mice lacking the Rho-inhibitory protein, p190-B RhoGAP, are 30% reduced in size and exhibit developmental defects strikingly similar to those seen in mice lacking the CREB transcription factor. In p190-B RhoGAP-deficient mice, CREB phosphorylation is substantially reduced in embryonic tissues. Embryo-derived cells contain abnormally high levels of active Rho protein, are reduced in size, and exhibit defects in CREB activation upon exposure to insulin or IGF-1. The cell size defect is rescued by expression of constitutively activated CREB, and in wild-type cells, expression of activated Rho or dominant-negative CREB results in reduced cell size. Together, these results suggest that activity of the Rho GTPase modulates a signal from insulin/IGFs to CREB that determines cell size and animal size during embryogenesis.

Animals↗

PubMed2002

The retinoblastoma tumour suppressor in development and cancer.

Since its discovery, the retinoblastoma (RB) tumour-suppressor protein has been a focal point of cancer research. Accumulating evidence indicates a complex role for RB in cell proliferation, differentiation and survival. To further complicate matters, proteins that are related to RB have redundant as well as antagonistic functions. Recent studies of knockout mice and cells that lack one or more of these proteins have begun to clarify their various context-specific functions and the unique activity of this tumour suppressor.

Animals↗