Bax alpha perturbs T cell development and affects cell cycle entry of T cells.

Brady, Hugh J.M.; Gil‐Gómez, Gabriel; Kirberg, Jörg; Berns, Anton

doi:10.1002/j.1460-2075.1996.tb01091.x

Cited by 162 publications

(124 citation statements)

References 56 publications

(83 reference statements)

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“…In T cell populations from baxaexpressing transgenic mice, it was found that entry into S phase (from quiescence) was accelerated, in comparison to controls (Brady et al, 1996), whereas the opposite e ect (i.e., delayed S phase entry) was observed in bcl-2-expressing transgenic mice (also from a quiescent state) (O'Reilly et al, 1996). From these observations one might begin to form a model in which enhancement or attenuation of cell cycle progression is associated with pro-or anti-apoptotic members of the family, respectively.…”

Section: Discussionmentioning

confidence: 98%

Expression of Bcl-XS alters cytokinetics and decreases clonogenic survival in K12 rat colon carcinoma cells

Fridman

Rehemtulla

Hofmann³

et al. 1998

Oncogene

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bcl-XS, a member of the bcl-2 family, has been shown to induce and/or sensitize some cells to undergo programmed cell death, and to negate the anti-apoptotic activity of bcl-XL and bcl-2 by mechanisms which are still uncertain. To help understand these mechanisms we have established stable derivatives of the K12 rat colon carcinoma cell line that express bcl-XS in a tetracyclineregulated manner, using an autoregulatory retroviral cassette. When bcl-XS expression is induced, we observe two phenotypic responses. A small fraction of cells appear to undergo spontaneous apoptosis while the majority of cells undergo a form of cytostasis. In the latter case, the cells stop dividing (or divide a limited number of times at a retarded rate) and swell to many times their original size. These cells can take on a ghostlike appearance and subsequently detach from the culture plates and die or they may remain intact in a hindered state of proliferation. Doubling times were calculated to be 31.4 h in the presence of tetracycline and 50.4 h without tetracycline, bcl-XS expression also causes dramatic alterations in the cell cycle distribution of K12 cells manifesting as a substantial decrease (&50%) in the fraction of S phase cells with a concomitant increase in the G1 population. Continuous expression of bcl-XS, at levels approximately equal to that of bcl-XL, decreased the viability of K12 cells as demonstrated by a log decline in clonogenic survival. This decrease occurred without considerable apoptosis or a compensatory increase in the level of bcl-XL. None of these phenotypes were present in control cells expressing b-galactosidase in a similar retroviral cassette. These observations demonstrate that bcl-XS can have substantial cytokinetic e ects under circumstances that produce relatively little apoptosis.

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Section: Discussionmentioning

confidence: 98%

Expression of Bcl-XS alters cytokinetics and decreases clonogenic survival in K12 rat colon carcinoma cells

Fridman

Rehemtulla

Hofmann³

et al. 1998

Oncogene

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“…Since apoptosis in other systems has been shown to be protein synthesis-dependent (Brady et al 1996b), we investigated whether mAb 225-mediated apoptosis require on-going protein synthesis. DiFi cells were treated with mAb 225 in the presence or absence of cycloheximide, and cell extracts were assayed for the induction of apoptosis.…”

Section: Mab 225-induced Apoptosis Is Accompanied By Increased Expresmentioning

confidence: 99%

Nuclear targeting of Bax during apoptosis in human colorectal cancer cells

et al. 1998

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Homeostasis in colonic epithelial cells is regulated by the balance between proliferative activity and cell loss by apoptosis. Because epithelial cells at the apex of colonic crypts undergo apoptosis and proliferative activity is usually restricted to the base of the crypts, it has been proposed that the limited availability of growth factorsignals at the upper portions of the crypts may trigger apoptosis. In the present studies, we investigate the mechanism of apoptosis mediated by growth factor deprivation in colorectal carcinoma cells by delineating the possible involvement of Bax and its subcellular localization. We report that inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase activity and downregulation of EGFR by anti-EGFR mAb 225 induces apoptosis in human colorectal carcinoma DiFi and FET cells. Induction of apoptosis was preceded by enhanced expression of newly synthesized Bax protein, and required protein synthesis. In the mAb 225-treated cells, Bax was redistributed from the cytosol to the nucleus and subsequently, to the nuclear membranes. The observed induction of Bax expression by mAb 225 was not associated with p53 induction. However, mAb 225 treatment also triggered relocalization of p53 from the cytosol to a nuclear membrane-bound form. Induction of Bax and its redistribution to the nucleus of DiFi cells during apoptosis was also demonstrated in response to butyrate, a physiological relevant molecule in colonic epithelial cells as it is the principal short-chain fatty acid produced by bacterial fermentation of dietary ®ber in colonic epithelium. Using immuno¯uorescence and confocal microscopy, we observed that Bax is predominantly localized in the cytosol, but during apoptosis it is localized both inside and along the nuclear membrane. Taken together, these ®ndings suggest that apoptosis induced by growth factor-deprivation or butyrate may involve the subcellular redistribution of Bax in human colorectal carcinoma cells.

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“…For instance, apoptosis regulatory proteins of the Bcl-2 family have been shown to modulate cell-cycle progression. In particular, overexpression of the anti-apoptotic members of this family in B and T cells delays entry into S-phase [5][6][7] and accelerates withdrawal from the cell cycle [8,9]. In contrast, overexpression of pro-apoptotic members such as Bax or Bad in T cells of transgenic mice increases the number of cycling thymocytes, favouring entry into S-phase [6,10].…”

Section: Introductionmentioning

confidence: 99%

Bcl-2 activates a programme of premature senescence in human carcinoma cells

Crescenzi

Palumbo

Brady

2003

Biochemical Journal

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The apoptosis regulator Bcl-2 has been shown to modulate cellcycle progression, favouring a quiescent state over a proliferative state, in both normal and tumour cells. We show here that constitutive expression of Bcl-2 in human carcinoma cells results in a cell-cycle arrest that within a few days can become irreversible. Arrested cells acquire a senescent-like phenotype, which consists of several characteristic morphological alterations and increased activity of senescence-associated β-galactosidase. The induction of the premature senescence programme is mediated by inhibition of Cdk2 kinase activity, and p27 KIP1 is required to maintain the senescent phenotype. We propose that the ability to activate an endogenous premature senescence programme allows Bcl-2 to suppress tumour growth. These results suggest that the downregulation of Bcl-2 expression, which has been observed during the development and progression of human carcinoma, is related to the ability of Bcl-2 to severely hamper the growth of carcinoma cells and to induce a permanent cell-cycle arrest, with the features of senescence.

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Bax alpha perturbs T cell development and affects cell cycle entry of T cells.

Cited by 162 publications

References 56 publications

Expression of Bcl-XS alters cytokinetics and decreases clonogenic survival in K12 rat colon carcinoma cells

Expression of Bcl-XS alters cytokinetics and decreases clonogenic survival in K12 rat colon carcinoma cells

Nuclear targeting of Bax during apoptosis in human colorectal cancer cells

Bcl-2 activates a programme of premature senescence in human carcinoma cells

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