Cellular Response to Oncogenic Ras Involves Induction of the Cdk4 and Cdk6 Inhibitor p15<sup><i>INK4b</i></sup>

Malumbres, Marcos; Castro, Ignacio Pérez de; Hernández, María Inmaculada; Jiménez, María; Corral, Teresa; Pellicer, Ángel Antonio Blasco

doi:10.1128/mcb.20.8.2915-2925.2000

Cited by 154 publications

(123 citation statements)

References 71 publications

Supporting

Mentioning

114

Contrasting

Unclassified

Order By: Relevance

“…Levels of expression of other CKIs, p27, p57, and p14 ARF , were also examined and found not to change. The mRNA levels of p15, another CKI implicated in senescence and Ras-induced arrest (Malumbres et al, 2000) were also found to be relatively unchanged. These results indicate that Rafinduced arrest of finite lifespan human epithelial cells does not require increased expression of the CKIs whose increased expression is associated with fibroblast senescence.…”

Section: Resultsmentioning

confidence: 89%

Raf-1-induced growth arrest in human mammary epithelial cells is p16-independent and is overcome in immortal cells during conversion

et al. 2002

View full text Add to dashboard Cite

Using an estrogen-inducible retroviral system, we demonstrate that oncogenic Raf-1 induces growth arrest and morphological changes in finite lifespan human mammary epithelial cells (HMEC). This arrest does not rely on expression of the cyclin-dependent kinase inhibitor (CKI) p16 INK4a , nor on changes in expression of the CKIs p21 Cip1 , p14 ARF , p27 Kip1 or p57 Kip2 . The Raf-induced arrest is independent of viral oncogene mediated inactivation of p53 and pRB, or c-myc overexpression. Flow cytometric analysis demonstrates that cells arrest in both G1 and G2. The Raf-induced arrest is mitigated or eliminated in some immortally transformed HMEC. Immortal HMEC that have both overcome replicative senescence and undergone the recently described conversion process maintain growth in the presence of transduced oncogenic Raf-1; they also gain EGF-independent growth and a low frequency of anchorage-independent growth. However, HMEC that have overcome replicative senescence but have not undergone conversion and HMEC immortalized by transduction with the catalytic subunit of telomerase, hTERT, remain severely growth arrested. These results indicate that the molecular mechanisms responsible for the Raf-1-induced growth arrest may vary among different finite lifespan cell types, and that in HMEC, this mechanism is altered during the conversion process, rather than as a direct consequence of overcoming senescence or expressing hTERT.

show abstract

Section: Resultsmentioning

confidence: 89%

Raf-1-induced growth arrest in human mammary epithelial cells is p16-independent and is overcome in immortal cells during conversion

et al. 2002

View full text Add to dashboard Cite

show abstract

“…As a CDK4/6 inhibitor, p15 INK4b overexpression is sufficient to induce a cellular senescent phenotype in cultured primary cells of early passages [24], as well as in human tumor cells [25]. Moreover, p15 INK4b up-regulation is responsible for the cellular senescence induced by oncogenic Ras and for the inhibition of cellular transformation [26]. The role of the CDK2 inhibitor p27 KIP1 in cellular senescence has been reported in some particular tumors in vivo.…”

Section: Discussionmentioning

confidence: 99%

Senescence of human skin-derived precursors regulated by Akt-FOXO3-p27KIP1/p15INK4b signaling

Liu

Wang

Zhao

et al. 2015

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Multipotent skin-derived precursors (SKPs) are dermal stem cells with the capacity to reconstitute the dermis and other tissues, such as muscles and the nervous system. Thus, the easily available human SKPs (hSKPs) hold great promises in regenerative medicine. However, long-term expansion is difficult for hSKPs in vitro. We previously demonstrated that hSKPs senesced quickly under routine culture conditions. To identify the underlying mechanisms so as to find an effective way to expand hSKPs, time-dependent microarray analysis of gene expression in hSKPs during in vitro culture was performed. We found that the senescence of hSKPs had a unique gene expression pattern that differs from reported typical senescence. Subsequent investigation ruled out the role of DNA damage and classical p53 and p16 INK4a signaling in hSKP senescence. Examination of cyclin-dependent kinase inhibitors revealed the involvement of p15 INK4b and p27 KIP1 . Further exploration about upstream signals indicated the contribution of Akt hypo-activity and FOXO3 to hSKP senescence. Forced activation of Akt and knockdown of FOXO3, p15 INK4b and p27 KIP1 effectively inhibited hSKP senescence and promoted hSKP proliferation. The unique senescent phenotype of human dermal stem cells and the role of Akt-FOXO3-p27 KIP1 /p15 INK4b signaling in regulating hSKP senescence provide novel insights into the senescence and self-renewal regulation of adult stem cells. The present study also points out a way to propagate hSKPs in vitro so as to fulfill their promises in regenerative medicine.

show abstract

“…In cells that have lost tumor suppressors, their reconstitution can render the cells resistant to oncogenic stimuli. p16 Ink4a and p15 Ink4b were able to suppress cellular transformation by Ras in mouse embryo fibroblasts (MEFs) that had targeted homologous deletion at the respective locus (Serrano et al, 1995;Malumbres et al, 2000b).…”

Section: Introductionmentioning

confidence: 99%

Consistent inactivation of p19Arf but not p15Ink4b in murine myeloid cells transformed in vivo by deregulated c-Myc

Haviernik

Schmidt

et al. 2003

Oncogene

View full text Add to dashboard Cite

Cyclin-dependent kinase inhibitors p16 INK4a and p15 INK4b , encoded by the CDKN2A and B loci, play an important role in negative regulation of the cell cycle. Furthermore, p19 ARF also encoded by the CDKN2A locus, has been shown to regulate positively the p53 pathway leading to growth arrest and apoptosis. All three genes have been inactivated in human tumors. In myeloid cells, p15 INK4b mRNA is upregulated during cytokine-induced differentiation and/or growth arrest, and hypermethylation of the p15 INK4b gene promoter region is a common event in acute myeloid leukemia. In the present study, we examined murine monocyte/macrophage tumors with deregulated cmyc for evidence of Ink4 gene inactivation. p15 Ink4b mRNA and protein were detected in the majority of leukemias, and p16 Ink4a mRNA and protein were highly expressed in two of them. pRb was in a hypophosphorylated state in most of the neoplasms indicating that the Cdk inhibitors that were expressed in the cells were functional. The observed expression of p15 Ink4b is inconsistent with their proliferation state, although it might be expected to be expressed owing to the maturity of the cells. These data suggest, therefore, that deregulated cMyc bypasses the pRb restriction point and cell cycle arrest in these tumors. An examination of p19 Arf exons revealed deletions of the gene in up to 94% of the tumors. Since this gene shares exon 2 with p16 Ink4a , it is often difficult to determine which gene is the relevant tumor suppressor. However, the loss of only the p19 Arf -specific exon 1b was observed in a tumor that had normal p16 Ink4a protein expression. In addition, the p19 Arf -specific exon was deleted in another tumor that expressed a functional chimeric protein, p15Ex1-p16Ex2-3; it was demonstrated here that this fusion protein is capable of inducing G1 arrest. These data overall supports the hypothesis that the critical inactivation event in these hematopoietic neoplasms is elimination of p19 Arf , and not Ink4 function.

show abstract

Cellular Response to Oncogenic Ras Involves Induction of the Cdk4 and Cdk6 Inhibitor p15^INK4b

Cited by 154 publications

References 71 publications

Raf-1-induced growth arrest in human mammary epithelial cells is p16-independent and is overcome in immortal cells during conversion

Raf-1-induced growth arrest in human mammary epithelial cells is p16-independent and is overcome in immortal cells during conversion

Senescence of human skin-derived precursors regulated by Akt-FOXO3-p27KIP1/p15INK4b signaling

Consistent inactivation of p19Arf but not p15Ink4b in murine myeloid cells transformed in vivo by deregulated c-Myc

Contact Info

Product

Resources

About

Cellular Response to Oncogenic Ras Involves Induction of the Cdk4 and Cdk6 Inhibitor p15INK4b

Cited by 154 publications

References 71 publications

Raf-1-induced growth arrest in human mammary epithelial cells is p16-independent and is overcome in immortal cells during conversion

Raf-1-induced growth arrest in human mammary epithelial cells is p16-independent and is overcome in immortal cells during conversion

Senescence of human skin-derived precursors regulated by Akt-FOXO3-p27KIP1/p15INK4b signaling

Consistent inactivation of p19Arf but not p15Ink4b in murine myeloid cells transformed in vivo by deregulated c-Myc

Contact Info

Product

Resources

About

Cellular Response to Oncogenic Ras Involves Induction of the Cdk4 and Cdk6 Inhibitor p15^INK4b