Transcriptional Profiling of Krüppel-like Factor 4 Reveals a Function in Cell Cycle Regulation and Epithelial Differentiation

Chen, Xinming; Whitney, Erika M.; Gao, Shu Ying; Yang, Vincent W.

doi:10.1016/s0022-2836(02)01449-3

Cited by 179 publications

(177 citation statements)

References 89 publications

Supporting

Mentioning

162

Contrasting

Order By: Relevance

“…Remarkably, KLF4 had opposing effects on the cyclin-dependent kinase inhibitor p21 CIP1 and on p53. First, KLF4 expression led to an increase in p21 CIP1 levels (a finding that corresponds with previously reported data 3,6 ; Fig. 2a), which occurred independently of p53 (Fig.…”

Section: Klf4 Suppresses P53 But Induces P21 Cip1supporting

confidence: 90%

The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene

2005

View full text Add to dashboard Cite

KLF4 (GKLF/EZF) encodes a transcription factor that is associated with both tumour suppression and oncogenesis. We describe the identification of KLF4 in a functional genomic screen for genes that bypass RAS V12 -induced senescence. However, in untransformed cells, KLF4 acts as a potent inhibitor of proliferation. KLF4-induced arrest is bypassed by oncogenic RAS V12 or by the RAS target cyclin-D1. Remarkably, inactivation of the cyclin-D1 target and the cell-cycle inhibitor p21 CIP1 not only neutralizes the cytostatic action of KLF4, but also collaborates with KLF4 in oncogenic transformation. Conversely, KLF4 suppresses the expression of p53 by directly acting on its promoter, thereby allowing for RAS V12 -mediated transformation and causing resistance to DNA-damage-induced apoptosis. Consistently, KLF4 depletion from breast cancer cells restores p53 levels and causes p53-dependent apoptosis. These results unmask KLF4 as a regulator of p53 that oncogenically transforms cells as a function of p21 CIP1 status. Furthermore, they provide a mechanistic explanation for the context-dependent oncogenic or tumour-suppressor functions of KLF4.Krüppel-like factor 4 (KLF4/GKLF/EZF) 1,2 is a transcription factor that can both activate and repress genes that are involved in cell-cycle regulation and differentiation. Among the KLF4-regulated cell-cycle genes, many upregulated genes are inhibitors of proliferation, whereas genes that promote proliferation are repressed 3 . This indicates that KLF4 regulates the expression of a set of cell-cycle genes to coordinately inhibit cellular proliferation. In keeping with this is the notion that ectopic expression of KLF4 acts cytostatically 1,4,5 . Moreover, KLF4 levels rise following DNA damage, cell-cycle arrest in response to serum withdrawal and contact inhibition 1,6 . Similarly, KLF4 levels are increased in the post-mitotic compartment of the gut and skin 1,2 . In mice, ectopic expression of Klf4 accelerates terminal differentiation, leading to premature skin-barrier acquisition 7 , whereas Klf4 deficiency prevents the terminal differentiation of colonic goblet cells 8 and the skin epithelium 9 , which leads to neonatal death 9 . These observations establish KLF4 as a stress-and differentiation-associated inhibitor of proliferation 10 , raising the possibility that KLF4 may have tumour-suppressive functions 8,11,12 .Indeed, KLF4 expression is frequently lost in various human cancer types 11,[13][14][15][16][17][18][19] . Recently, KLF4 has been shown to undergo promoter methylation and loss of heterozygosity in gastrointestinal cancer 16,17 . Consistent with a tumour-suppressor function for KLF4, its overexpression reduces the tumorigenicity of colonic and gastric cancer cells in vivo 17,20 . These observations, taken together, indicate that KLF4 acts as a tumour suppressor. This notion is further supported by recent data showing that specific ablation of Klf4 in the gastric epithelium of mice results in premalignant changes, including polypoid lesions 18 .Conversely, elevated K...

show abstract

Section: Klf4 Suppresses P53 But Induces P21 Cip1supporting

confidence: 90%

The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene

2005

View full text Add to dashboard Cite

show abstract

“…KLF4 accomplishes this task both through its transcriptional activation of p21 WAF1/Cip1 and through direct suppression of cyclin D1 [19] and cyclin B1 expression [18], which are required for the G 1 /S and G 2 /M transitions, respectively. Expression profiling of KLF4 using cDNA microarray analysis confirmed that KLF4 activates transcription of many additional genes encoding inhibitors of the cell cycle and suppresses those encoding promoters of the cell cycle [20]. Recent studies from our laboratory indicate that KLF4 is also involved in preventing centrosome amplification after γ irradiation [21] and possibly in preventing aneuploidy after spindle damage (Dalton and Yang, unpublished observations).…”

Section: Klf4 and 5 Exhibit Contrasting Effects On Cellular Proliferamentioning

confidence: 69%

“…KLF4 then exerts a multitude of effects on expression of downstream genes by activating ( ) or inhibiting their expression ( ). References in support of the specific pathways are as follows: p53 KLF4 p21 [16]; KLF4 cyclin D/Cdk4 [19]; KLF4 cyclin B/Cdc2 [18]; KLF4 cyclin E/Cdk2 [21]; KLF4 STK15 [20]; KLF4 14-3-3 σ ; KLF4 BUB1/MAD2 [20].…”

Section: Klf4 and Klf5 Exert Distinct Physiologic Functions In Vivo Amentioning

confidence: 99%

See 1 more Smart Citation

Krüppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation

et al. 2005

Self Cite

View full text Add to dashboard Cite

Krüppel-like factors (KLFs) are evolutionarily conserved zinc finger-containing transcription factors with diverse regulatory functions in cell growth, proliferation, differentiation, and embryogenesis. KLF4 and KLF5 are two closely related members of the KLF family that have a similar tissue distribution in embryos and adults. However, the two KLFs often exhibit opposite effects on regulation of gene transcription, despite binding to similar, if not identical, cis-acting DNA sequences. In addition, KLF4 and 5 exert contrasting effects on cell proliferation in many instances; while KLF4 is an inhibitor of cell growth, KLF5 stimulates proliferation. Here we review the biological properties and biochemical mechanisms of action of the two KLFs in the context of growth regulation.

show abstract

“…What are these activities, and how are they regulated by KLF4? CDKN1A, are involved in differentiation and cell-cycle inhibition 28 (TABLE 1). Klf4-knockout mice show defects in skin differentiation 29 as well as a reduced number of secretory goblet cells in the colon 30 , indicating that KLF4 functions as a proliferation-differentiation switch.…”

mentioning

confidence: 99%

KLF4, p21 and context-dependent opposing forces in cancer

2005

View full text Add to dashboard Cite

| Krüppel-like factors are transcriptional regulators that influence several cellular functions, including proliferation. Recent studies have shown that one family member, KLF4, can function both as a tumour suppressor and an oncogene. The ability of KLF4 to affect the levels of expression of the cell-cycle regulator p21 seems to be involved, in that this protein might function as a switch that determines the outcome of KLF4 signalling. Is this role of p21 restricted to KLF4, or does p21 represent a nodal point for signals from multiple other factors with opposing functions in cancer?

show abstract

Transcriptional Profiling of Krüppel-like Factor 4 Reveals a Function in Cell Cycle Regulation and Epithelial Differentiation

Cited by 179 publications

References 89 publications

The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene

The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene

Krüppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation

KLF4, p21 and context-dependent opposing forces in cancer

Contact Info

Product

Resources

About