Suppression of p160ROCK bypasses cell cycle arrest after Aurora-A/STK15 depletion

Du, Jinyan; Hannon, Gregory J.

doi:10.1073/pnas.0308484101

Cited by 71 publications

(65 citation statements)

References 46 publications

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“…The protein serine/threonine kinases Rho-kinases (or ROCK) are downstream effectors of Rho able to selectively interact with the GTP-bound form of Rho. Moreover, it has recently been demonstrated that p160ROCK is a centrosome component, which functions in centrosome positioning 31 and also with Aurora A controls progression through G2/M, 42 which suggest that this protein may mediate the radioprotective effect of RhoB-F. We have shown that treatment of RhoB-F-expressing cells with the ROCK inhibitor, Y27632, activated mitotic cell death mechanisms and centrosome overduplication after irradiation. The same treatment though has no effect on RhoB-GG cells.…”

Section: Discussionmentioning

confidence: 78%

Farnesylated RhoB inhibits radiation-induced mitotic cell death and controls radiation-induced centrosome overduplication

et al. 2005

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Our previous results demonstrated that expressing the GTPase ras homolog gene family, member B (RhoB) in radiosensitive NIH3T3 cells increases their survival following 2 Gy irradiation (SF2). We have first demonstrated here that RhoB expression inhibits radiation-induced mitotic cell death. RhoB is present in both a farnesylated and a geranylgeranylated form in vivo. By expressing RhoB mutants encoding for farnesylated (RhoB-F cells), geranylgeranylated or the CAAX deleted form of RhoB, we have then shown that only RhoB-F expression was able to increase the SF2 value by reducing the sensitivity of these cells to radiation-induced mitotic cell death. Moreover, RhoB-F cells showed an increased G2 arrest and an inhibition of centrosome overduplication following irradiation mediated by the Rhokinase, strongly suggesting that RhoB-F may control centrosome overduplication during the G2 arrest after irradiation. Overall, our results for the first time clearly implicate farnesylated RhoB as a crucial protein in mediating cellular resistance to radiation-induced nonapoptotic cell death.

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Section: Discussionmentioning

confidence: 78%

Farnesylated RhoB inhibits radiation-induced mitotic cell death and controls radiation-induced centrosome overduplication

et al. 2005

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“…Overexpression or constitutive activation of Aurora-A, results after one or two division cycles in supernumerary centrosomes and multipolar mitotic spindles, dependent on an initial failure of cytokinesis: this is thought to be an important predetermining factor for genomic instability in many cancers (Marumoto et al, 2005). Although the mechanism by which Aurora-A amplification promotes cytokinetic failure remains to be determined, interestingly, Aurora-A and the RhoA effector p160ROCK have been shown to form a complex in mitotic cells, and siRNA depletion of p160ROCK blocked some Aurora-A-dependent defects (Du and Hannon, 2004). Hence, the association of HEF1 with Aurora-A provides a separate means by which Aurora-A might influence RhoA.…”

Section: Discussionmentioning

confidence: 99%

Deregulation of HEF1 Impairs M-Phase Progression by Disrupting the RhoA Activation Cycle

Dadke

Jarnik

Pugacheva

et al. 2006

MBoC

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The focal adhesion-associated signaling protein HEF1 undergoes a striking relocalization to the spindle at mitosis, but a function for HEF1 in mitotic signaling has not been demonstrated. We here report that overexpression of HEF1 leads to failure of cells to progress through cytokinesis, whereas depletion of HEF1 by small interfering RNA (siRNA) leads to defects earlier in M phase before cleavage furrow formation. These defects can be explained mechanistically by our determination that HEF1 regulates the activation cycle of RhoA. Inactivation of RhoA has long been known to be required for cytokinesis, whereas it has recently been determined that activation of RhoA at the entry to M phase is required for cellular rounding. We find that increased HEF1 sustains RhoA activation, whereas depleted HEF1 by siRNA reduces RhoA activation. Furthermore, we demonstrate that chemical inhibition of RhoA is sufficient to reverse HEF1-dependent cellular arrest at cytokinesis. Finally, we demonstrate that HEF1 associates with the RhoA-GTP exchange factor ECT2, an orthologue of the Drosophila cytokinetic regulator Pebble, providing a direct means for HEF1 control of RhoA. We conclude that HEF1 is a novel component of the cell division control machinery and that HEF1 activity impacts division as well as cell attachment signaling events. INTRODUCTIONAs points of structural linkage between the extracellular matrix (ECM) and the intracellular cytoskeleton, focal adhesions possess a complex function. For example, during migration, cells must rapidly break down and reform adhesions with the ECM, providing force for propulsion (Lauffenburger and Horwitz, 1996). At mitotic entry, cultured cells round up and decrease adhesion to the ECM; at mitotic exit, basal attachments reassemble and contribute to the force generation required for efficient progress through cytokinesis and reentry into G 1 . In interphase cells, the formation of novel focal adhesion-ECM interactions can specify cellular differentiation by activating specific signaling cascades culminating in the induction of differentiationpromoting transcription factors, and in parallel enforce removal from the cell cycle (Boudreau and Bissell, 1998). In many cell types, sustained loss of adhesion is a sufficient stimulus to induce apoptosis (anoikis) (Frisch and Francis, 1994), a surveillance mechanism against cancer, inhibiting the formation of micrometastases. Hence, one frequent effect of oncogenic transformation is the circumvention of the adhesion-viability coupling, leading to acquisition by cancer cells of the ability to grow in an anchorage-independent manner (Schwartz, 1997). Based on these diverse biological roles, there has been considerable research effort directed at elucidating the signaling role of focal adhesion-associated proteins (Schlaepfer et al., 1999).HEF1, p130Cas, and Efs/Sin define the Cas family of proteins Bouton et al., 2001). In interphase cells, Cas proteins predominantly localize to focal adhesions. During initial integrin engagement, induced by cell a...

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“…On the other hand, ROCK1 physically associates with STK15, which is implicated in the regulation of the centrosome replication cycle. Suppression of ROCK1 expression by siRNA bypasses G(2)/M cell cycle arrest after STK15 depletion and alleviates apoptosis in HeLa cells [25].…”

Section: In Vitro Evidencementioning

confidence: 99%

“…The small GTP-binding protein RhoE interacts with the N-terminal region of ROCK1 (amino acids 1-420) and prevents Rho binding to RBD [101,112]. Other negative regulators have been found to bind to and inhibit ROCK activity, such as the small GTP-binding proteins, Gem and Rad [145], Raf-1 [107], p21(Cip1/WAF1) [81] and Aurora-A/serine/threonine kinase 15 (STK15) [25]. However, their mechanisms of action are not defined.…”

Section: Regulation Of Rock Activitymentioning

confidence: 99%

Rho kinase in the regulation of cell death and survival

Shi

Wei

2007

Arch. Immunol. Ther. Exp.

214

183

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SummaryRho kinase (ROCK) belongs to a family of serine/threonine kinases that are activated via interaction with Rho GTPases. ROCK is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, and proliferation. Recent studies have shown that ROCK plays an important role in the regulation of apoptosis in various cell types and animal disease models. Two ROCK isoforms, ROCK1 and ROCK2, are assumed to be function redundant, based largely on kinase construct overexpression, and chemical inhibitors (Y27632 and fasudil), which inhibit both ROCK1 and ROCK2. Gene targeting and RNA interference approaches allow further dissection of distinct cellular, physiological and patho-physiological functions of the two ROCK isoforms. This review, based on recent molecular, cellular and animal studies, focuses on the current understanding of ROCK signaling in the regulation of apoptosis and highlights the new findings from recently generated ROCK-deficient mice.

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Suppression of p160ROCK bypasses cell cycle arrest after Aurora-A/STK15 depletion

Cited by 71 publications

References 46 publications

Farnesylated RhoB inhibits radiation-induced mitotic cell death and controls radiation-induced centrosome overduplication

Farnesylated RhoB inhibits radiation-induced mitotic cell death and controls radiation-induced centrosome overduplication

Deregulation of HEF1 Impairs M-Phase Progression by Disrupting the RhoA Activation Cycle

Rho kinase in the regulation of cell death and survival

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