RESEARCH ABSTRACTS:

 


Goberdhan P. Dimri, A. Testori, Meileen Acosta, Judith Campisi "Replicative Senescence, Aging and Growth-Regulatory Transcription Factors" Biol Signals. 1996, 5:154-162

Normal somatic cells invariably enter a state of permanent growth arrest and altered function after a finite number of divisions. This phenomenon is termed cellular or replicative senescence. Replicative senescence is thought to be a tumor-suppressive mechanism, and a contributing factor in aging. Three features distinguish senescent from presenescent cells: an irreversible block to cell proliferation, increased resistance to apoptotic death, and changes in differentiated functions. Senescence entails an altered pattern of gene expression, much of which is due to altered transcription. At least three growth regulatory transcriptional modulators are repressed in senescent cells: the c-fos component of the AP-1 transcription factor, the Id1 and Id2 helix-loop-helix (HLH) proteins that negatively regulate basic HLH transcription factors, and the E2F-1 component of the E2F transcription factor. Failure to express any one of these modulators is very likely sufficient to arrest cell proliferation. Loss of these modulators may also explain many of the functional changes shown by senescent cells. In the case of c-fos repression, the resulting decline in AP-1 activity may be exacerbated by an altered ratio of AP-1 components to a protein known as QM or Jif. QM interacts with the c-jjun component of AP-1 and suppresses AP-1 activity. We cloned QM from a senescent fibroblast cDNA library, and found that it was neither cell cycle- nor senescence-regulated. However, QM suppressed the growth of murine and human fibroblasts when overexpressed. Thus, an altered balance between positive factors (e.g., API components) and negative factors (e.g., QM) may lead to the growth arrest, as well as the changes in differentiated gene expression, that are a hallmark of senescent cells.


Goberdhan P. Dimri, Koji Itahana, Meileen Acosta, And Judith Campisi. "Regulation of a Senescence Checkpoint Response by the E2F1 Transcription Factor and pl4ARF Tumor Suppressor" Mol.Cell.Bio, Jan. 2000, 20(1):273 — 285.

Normal cells do not divide indefinitely due to a process known as replicative senescence. Human cells arrest growth with a senescent phenotype when they acquire one or more critically short telomeres as a consequence of cell division. Recent evidence suggests that certain types of DNA damage, chromatin remodeling, and oncogenic forms of Ras or Raf can also elicit a senescence response. We show here that E2F1, a multifunctional transcription factor that binds the retinoblastoma (pRb) tumor suppressor and that can either promote or suppress tumorigenesis, induces a senescent phenotype when overexpressed in normal human fibroblasts. Normal human cells stably arrested proliferation and expressed several markers of replicative senescence in response to E2F1. This activity of E2F1 was independent of its pRb binding activity but dependent on its ability to stimulate gene expression. The E2F1 target gene critical for the senescence response appeared to be the p14ARF tumor suppressor. Replicatively senescent human fibroblasts overexpressed p14ARF and ectopic expression of p14 in presenescent cells induced a phenotype similar to that induced by E2F1. Consistent with a critical role for p14ARF , cells with compromised p53 function were immune to senescence induction by E2F1, as were cells deficient in p14ARF. Our findings support the idea that the senescence response is a critical tumor-suppressive mechanism, provide an explanation for the apparently paradoxical roles of E2F1 in oncogenesis, and identity pl4ARF as a potentially important mediator of the senescent phenotype.