The small GTPase Cdc42 initiates an apoptotic signaling pathway in Jurkat T lymphocytes.

Abstract

Apoptosis plays an important role in regulating development and homeostasis of the immune system, yet the elements of the signaling pathways that control cell death have not been well defined. When expressed in Jurkat T cells, an activated form of the small GTPase Cdc42 induces cell death exhibiting the characteristics of apoptosis. The death response induced by Cdc42 is mediated by activation of a protein kinase cascade leading to stimulation of c-Jun amino terminal kinase (JNK). Apoptosis initiated by Cdc42 is inhibited by dominant negative components of the JNK cascade and by reagents that block activity of the ICE protease (caspase) family, suggesting that stimulation of the JNK kinase cascade can lead to caspase activation. The sequence of morphological events observed typically in apoptotic cells is modified in the presence of activated Cdc42, suggesting that this GTPase may account for some aspects of cytoskeletal regulation during the apoptotic program. These data suggest a means through which the biochemical and morphological events occurring during apoptosis may be coordinately regulated.

Extinction of Rac1 and Cdc42Hs signalling defines a novel p53-dependent apoptotic pathway

“…However, numerous signalling molecules induce apoptosis independently of p53 activity. Interestingly, unlike the situation reported here, the constitutively active form of Cdc42Hs (Cdc42HsV12) signals apoptosis in a p53 independent manner (Chuang et al, 1997).…”

“…More recently, it has been demonstrated that these proteins are also implicated in apoptosis control (Bazenet et al, 1998;Chuang et al, 1997;Donovan et al, 1997;Fort, 1999 and references therein). Whereas these studies report a role for activated Rho, Rac and Cdc42Hs in apoptosis regulation, we show here that expression of the dominant negative forms of Rac1 and Cdc42Hs are also potent inducers of apoptosis.…”

“…Similarly, mice harbouring a transgene encoding the constitutively activated Rac GTPase, whose expression is targeted to early T lymphocyte precursors, su er severe thymic atrophy due to elevated thymocyte apoptosis. It has also been reported that the constitutively active mutant of Cdc42Hs (Cdc42HsV12) induces apoptosis in the human leukaemic Jurkat T cells (Chuang et al, 1997). The molecular mechanisms of apoptosis induction by the activated forms of these GTPases are unknown.…”

Statins induce apoptosis in ovarian cancer cells through activation of JNK and enhancement of Bim expression

“…Interestingly, these small GTPases are found to mediate apoptosis in a wide-range of cell types. Overexpression of active Cdc42 in Jurkat T lymphocytes induces increased ceramide levels, resulting in cell death [29,30]. Both Rac1 and Cdc42 mediate apoptosis induced by diverse stimuli [31].…”

“…Both Rac1 and Cdc42 mediate apoptosis induced by diverse stimuli [31]. It seems that the contribution of Rac1 and Cdc42 to apoptosis is to regulate mainly activa tion of the JNK pathway [32][33][34].…”