Phosphorylation and nuclear exclusion of the forkhead transcription factor FKHR after epidermal growth factor treatment in human breast cancer cells

Jackson, James G.; Kreisberg, Jeffrey I.; Koterba, Alan; Yee, Douglas; Brattain, Michael G.

doi:10.1038/sj.onc.1203825

Cited by 80 publications

(51 citation statements)

References 38 publications

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“…FKHR could not be detected in N.1 clones and AFX did not exhibit a distinct phosphorylation pattern in the cell clones analysed (data not shown). In N.1 cells, FKHRL1 accumulated in the nucleus under serumstarved conditions, which was also shown by others in different cell systems, 21,22 and nuclear expression of FKHRL1 was further increased in Cdc25A-overexpressing cells (Figure 2a, upper panel, compare lanes 1 and 5). It was demonstrated that 14.3.3 proteins bind to phosphorylated FKHRL1 (pFKHRL1) and cause its relocation from the nucleus into the cytoplasm 23,24 where it becomes rapidly degraded.…”

Section: Cdc25a Causes Dephosphorylation and Activation Of Fkhrl1supporting

confidence: 85%

Subcellular localisation of Cdc25A determines cell fate

et al. 2003

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Cell division cycle 25A (Cdc25A) was shown to colocalise both with nuclear and cytoplasmic proteins. Recently, we have demonstrated that overexpressed Cdc25A promoted the survival of rat 423 cells through indirect activation of PKBprotein kinase B. Using a Cdc25A:ER fusion protein, which can be shuttled from the cytoplasm into the nucleus, the present investigation evidences that the antiapoptotic effect of Cdc25A was restricted to its cytoplasmic localisation in rat 423 cells. In contrast, nuclear Cdc25A overexpression caused dephosphorylation and nuclear retention of the proapoptotic transcription factor Forkhead in rhabdomyosarcoma-like 1 (FKHRL1) in human N.1 ovarian carcinoma cells. This resulted in the increased constitutive expression of the FKHRL1 targets Fas ligand and Bim, and promoted apoptosis. Thus, the Cdc25A oncogene, which was found to be frequently overexpressed in certain human cancers, can increase or decrease the susceptibility to apoptosis depending on the cell-type-specific subcellular distribution.

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Section: Cdc25a Causes Dephosphorylation and Activation Of Fkhrl1supporting

confidence: 85%

Subcellular localisation of Cdc25A determines cell fate

et al. 2003

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“…(6, 44, or 23) was digested with EcoRI, separated in a 1% agarose gel and subjected to Southern analysis using an AKT1 probe Transgene expression under the control of the MMTV LTR is strongly induced during pregnancy (Krane and Leder, 1996). Since Akt is involved in multiple cell survival pathways that are relevant to mammary epithelium (Dufourny et al, 1997(Dufourny et al, , 2000Jackson et al, 2000;Lu et al, 1999;Zhou et al, 2000), the e ect of AKT1 overexpression in mammary epithelium during involution was examined. Female transgenic and non-transgenic littermates from founders 6 and 44, ranging in age from 16 ± 22 weeks, were bred and allowed to nurse their pups.…”

Section: Resultsmentioning

confidence: 99%

Delayed mammary gland involution in MMTV-AKT1 transgenic mice

et al. 2002

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AKT1/protein kinase Ba is a protein-serine/threonine kinase that regulates multiple targets involved in cell survival and cell cycle progression in a variety of cell types including breast cancer cells. To explore the role of Akt1 in mammary gland function and tumorigenesis, transgenic mice were generated that express human AKT1 under the control of the MMTV promoter. Virgin transgenic mice did not exhibit a dominant phenotype, but upon cessation of lactation, a notable delay in involution occurred compared to age-matched nontransgenic mice. The delay in involution coincided with increased hyperplasia as evidenced by an increased number of binucleated epithelial cells and a marked elevation in cyclin D1 expression in mammary epithelium. The delayed involution phenotype corresponded to increased phosphorylation of Thr308 in AKT1 and Ser136 in BAD, but not phosphorylation of Ser21 in GSK-3a. There was no evidence of mammary dysplasia or neoplasia during the lifespan of multiparous transgenic mice. These data suggest that AKT1 is involved in cell survival in the lactating and involuting mammary gland, but that overexpression of AKT1 alone is insu cient to induce transformation.

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“…[41][42][43][44] The PKB/AKT phosphorylates FKHR at 3 residues (Thr 24 , Ser 256 and Ser 319 ) by phosphoinositide 3-kinase (PI 3 K) pathway that results in the nuclear exit and inactivation of apoptosis related gene. [45][46][47] Furthermore, the expression of AKT resulted in phosphorylation of FKHR and translational upregulation of cyclin D1 levels. 48 At the same time, DYRK1A also phosphorylated FKHR, although on a different residue (Ser 329 ), and leads to the decrease of FKHR present in the nucleus.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of Dyrk1a in HPV16 immortalized Keratinocytes enable evasion of apoptosis

Chang

Lin

Yang

et al. 2007

Intl Journal of Cancer

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Immortalization is a critical event in virus-related oncogenesis. No enough information, however, is currently available to elucidate the changes that occur in cellular molecules during immortalization. To identify potential cellular markers or regulators involving in immortalization, a paired-cell model of primary foreskin keratinocytes (FK) and HPV16 immortalized foreskin keratinocytes were established. Using mRNA differential display, RT-PCR and Northern blot methods, we have identified and confirmed that Dyrk1a (dual-specificity tyrosine-phosphorylated and regulated kinase 1A) is present and increased in HPV16 immortalized cells, but is absent in primary keratinocytes. Moreover, transfection of E7 siRNA oligo into immortalized cells leads to a diminishing E7 expression and the eventual disappearance of Dyrk1a. Similar results of Dyrk1a expressional differences could also be seen when tissue specimens were compared using LCM/real-time PCR and immunohistochemistry analysis; malignant cervical lesions contain significantly more DYRK1A than normal tissue. It was also demonstrated that raised DYRK1A could rearrange the cellular localization of FKHR (forkhead in rhabdomyosarcoma), an apoptosis activator, and suppress BAD. Importantly, this phenomenon can be reversed when endogenous Dyrk1a was knocked down in immortalized cells by RNA interference. These results suggest that the raised Dyrk1a in HPV16 immortalized keratinocytes and cervical lesions may serve as a candidate antiapoptotic factor in the FKHR regulated pathway and initiate immortalization and tumorigenesis gradually. ' 2007 Wiley-Liss, Inc.Key words: HPV16; keratinocytes; Dyrk1a; immortalization; apoptosis Mammalian cells have a limited life span and proliferating capacity when cultivated in vitro. Replicate senescence or the terminal arrest state, has been found to be accompanied by several molecular changes that lead to an activated suppression of the cell cycle and the shortening of the telomeres. 1 Similar to apoptosis, cellular senescence is thought to be a mechanism of tumor suppression because it prevents the outgrowth of cells that have acquired mutations in genes rendering them cancerous. Consistent with this model, several tumor suppressor genes (such as, overexpressed p16 or ZNF217, activated p53 and deregulated Rassf1a or c-myc, etc) or their products have been reported and shown to be associated in parallel with telomere irregularities at the onset of cellular senescence. 2 Telomere shortening has been shown to generate unstable DNA leading to p53 activation and the subsequent transcriptional induction of the cdk inhibitor p21 CIP13 that moves cells into senescence state. Therefore, preventing telomere erosion by ectopic expression of telomerase is sufficient to immortalized primary cells in vitro and thus extend life span. [4][5][6] Although it works in human fibroblast, telemorase alone, however, is not sufficient to induce immortalization in human keratinocytes and mammary epithelial cells. 7 To identify other factors that are involved ...

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Phosphorylation and nuclear exclusion of the forkhead transcription factor FKHR after epidermal growth factor treatment in human breast cancer cells

Cited by 80 publications

References 38 publications

Subcellular localisation of Cdc25A determines cell fate

Subcellular localisation of Cdc25A determines cell fate

Delayed mammary gland involution in MMTV-AKT1 transgenic mice

Increased expression of Dyrk1a in HPV16 immortalized Keratinocytes enable evasion of apoptosis

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