Activation of cyclin A-dependent protein kinases during apoptosis.

Meikrantz, William; Gisselbrecht, Stephen S.; Tam, Sun W.; Schlegel, Robert

doi:10.1073/pnas.91.9.3754

Cited by 328 publications

(224 citation statements)

References 44 publications

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“…Overexpression of cyclin A has been shown to impede progression through mitosis and might facilitate apoptosis. 32 The expression of cell cycle regulatory proteins in malignant tumors is often analyzed to obtain prognostic information. High expression of proliferation markers, including Ki-67, PCNA, cyclin A and others, often have been associated with poor prognosis due to the high proliferation rate of the tumors.…”

Section: Discussionmentioning

confidence: 99%

Aberrant expression of cell cycle regulators in Hodgkin and Reed–Sternberg cells of classical Hodgkin's lymphoma

et al. 2005

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The characteristic Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma, although highly positive for proliferation markers, do not accumulate to excessive cell numbers. These cells are characterized by abortive mitotic cycles, leading to multinucleation or cell death in mitosis. We have previously described high expression of G 1 -phase cyclins in classical Hodgkin's lymphoma, which could explain the high percentage of cells staining for proliferation markers. To further our understanding of proliferation control in classical Hodgkin's lymphoma, we extended our immunohistochemical analysis to the main S-phase cyclin, cyclin A, and its regulators p21 CIP1 and p27 KIP1 . Expression of proliferating cell nuclear antigen (PCNA) was used as an additional marker for cells being in either S-or G 2 -phase. In 47% (112/239) of classical Hodgkin's lymphoma cases p21 CIP1 was detected within a mean frequency of 15% positive Hodgkin's and Reed-Sternberg cells per case. Similarly, 47% (116/249) of the cases stained positively for p27 KIP1 with a mean frequency of expression in Hodgkin's and Reed-Sternberg cells of 12%. In contrast, 90% of the cells in all 246 evaluable classical Hodgkin's lymphoma cases were positive for PCNA. In addition, 98% of Hodgkin's and Reed-Sternberg cells in 99% (250/253) of the cases stained strongly positive for cyclin A. These findings further corroborate the hypothesis that Hodgkin and Reed-Sternberg cells exhibit a disturbed cell cycle with an abnormally short or even absent G 1 -phase. In contrast to other tumors, expression of PCNA or cyclin A had no prognostic value for patient survival.

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Section: Discussionmentioning

confidence: 99%

Aberrant expression of cell cycle regulators in Hodgkin and Reed–Sternberg cells of classical Hodgkin's lymphoma

et al. 2005

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“…First, the ability to modulate Cdk2 is not limited to the antiapoptotic members of the Bcl-2 family but is also exhibited by pro-apoptotic proteins; for example, Bax [2]. In addition, even in resting cells, the activation of Cdk2 represents a key event for the induction of programmed cell death [2]; accordingly, activation of cyclin-Cdk2 complexes has been demonstrated during apoptosis in several cell types [49,50]. Hence we favour the hypothesis that the ability to modulate Cdk2 is relevant for the anti-apoptotic function of Bcl-2 in normal cells.…”

Section: Role Of Bcl-2-dependent Cell-cycle Regulation and Implicatiomentioning

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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“…Cells undergoing apoptosis often exhibit activation of cell cycle events, such as cdk activation and abortive cell cycle progression. 1,2 Many oncogenes have dual functions of positively regulating proliferation and apoptosis, such as Myc and E2F, whereas tumor suppressors, such as Rb and p53, inhibit cell cycle. BCL2 is an oncogene that inhibits apoptosis but, paradoxically, it is also antiproliferative.…”

Section: Introductionmentioning

confidence: 99%

BCL2 family in DNA damage and cell cycle control

2006

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Individual BCL2 family members couple apoptosis regulation and cell cycle control in unique ways. Antiapoptotic BCL2 and BCL-x L are antiproliferative by facilitating G0. BAX is proapoptotic and accelerates S-phase progression. The dual functions in apoptosis and cell cycle are coordinately regulated by the multi-domain BCL2 family members (MCL-1) and suggest that survival is maintained at the expense of proliferation. The role of BH3-only molecules in cell cycle is more variable. BAD antagonizes both the cell cycle and antiapoptotic functions of BCL2 and BCL-x L through BH3 binding. BID has biochemically separable functions in apoptosis and S-phase checkpoint, determined by posttranslational modification. p53-induced PUMA is known only to have apoptotic function. Inhibition of apoptosis is oncogenic, whereas promotion of cell cycle arrest is tumor suppressive. Paradoxically, selected BCL2 family members can be both oncogenic and tumor suppressive. Which of the dual functions predominates is lineage specific and context dependent.

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Activation of cyclin A-dependent protein kinases during apoptosis.

Abstract: Apoptosis was induced in S-phase-arrested

Cited by 328 publications

References 44 publications

Aberrant expression of cell cycle regulators in Hodgkin and Reed–Sternberg cells of classical Hodgkin's lymphoma

Aberrant expression of cell cycle regulators in Hodgkin and Reed–Sternberg cells of classical Hodgkin's lymphoma

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

BCL2 family in DNA damage and cell cycle control

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