Focal Adhesion Kinase Controls Cellular Levels of p27/Kip1 and p21/Cip1 through Skp2-Dependent and -Independent Mechanisms

Bryant, Patrick; Zheng, Qingyuan; Pumiglia, Kevin

doi:10.1128/mcb.01612-05

Cited by 65 publications

(60 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the deficiency in TAFs and altered ECM evident in the tumors from Fap-null and PT630-treated mice likely contribute to the reduction in tumor growth. This is further evidenced by the increase we observed in the CDK inhibitor p21 levels in tumors from Fap-null and PT630-treated mice, as p21 is known to regulate the ECMmediated signaling pathway that activates cell cycle progression (44). The excess collagen accumulation, in the face of the reduction in SMA-expressing myofibroblasts in these tumors, may appear, at first glance, contradictory to the fact that myofibroblasts are believed to be a major source of collagen.…”

Section: Discussioncontrasting

confidence: 42%

“…Indeed, we found that tumors from Fap-null mice compared with those from Fap wild-type mice and tumors from mice treated with PT630 but not with LAF237 compared with those from vehicle control-treated mice showed an increase in phospho-FAK Tyr397 and phospho-ERK (p44/42) ( Figure 6 and Supplemental Figure 7). Although phosphorylation of MAPK usually correlates with cell proliferation, it can also increase the expression of the cell cycle inhibitor p21 WAF1 protein, causing cell cycle arrest (44,45). We found that p21 WAF1 was indeed increased in FAP-null and PT630-treated tumors (P = 0.04; Figure 6 and Supplemental Figure 7).…”

Section: Lsl-k-rassupporting

confidence: 49%

See 1 more Smart Citation

Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice

Santos

Jung²,

Aziz³

et al. 2009

J. Clin. Invest.

376

357

View full text Add to dashboard Cite

Membrane-bound proteases have recently emerged as critical mediators of tumorigenesis, angiogenesis, and metastasis. However, the mechanisms by which they regulate these processes remain unknown. As the cell surface serine protease fibroblast activation protein (FAP) is selectively expressed on tumor-associated fibroblasts and pericytes in epithelial tumors, we set out to investigate the role of FAP in mouse models of epithelialderived solid tumors. In this study, we demonstrate that genetic deletion and pharmacologic inhibition of FAP inhibited tumor growth in both an endogenous mouse model of lung cancer driven by the K-ras G12D mutant and a mouse model of colon cancer, in which CT26 mouse colon cancer cells were transplanted into immune competent syngeneic mice. Interestingly, growth of only the K-ras G12D -driven lung tumors was also attenuated by inhibition of the closely related protease dipeptidyl peptidase IV (DPPIV). Our results indicate that FAP depletion inhibits tumor cell proliferation indirectly, increases accumulation of collagen, decreases myofibroblast content, and decreases blood vessel density in tumors. These data provide proof of principle that targeting stromal cell-mediated modifications of the tumor microenvironment may be an effective approach to treating epithelial-derived solid tumors.

show abstract

Section: Discussioncontrasting

confidence: 42%

Section: Lsl-k-rassupporting

confidence: 49%

Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice

Santos

Jung²,

Aziz³

et al. 2009

J. Clin. Invest.

376

357

View full text Add to dashboard Cite

show abstract

“…In addition, merlin reexpression in NF2-deficient malignant mesothelioma cells has been found to attenuate FAK phosphorylation and to inhibit the interaction between FAK and Src (41). While the exact mechanism underlying FAK growth regulation has not been elucidated fully, recent evidence suggests that FAK may control cell growth by suppressing p21 and p27 cyclin-dependent kinase inhibitor levels (6,12). However, in preliminary experiments, we detected no changes in p21 and p27 expression in Nf2 Ϫ/Ϫ glia relative to WT glia (S. S. Houshmandi and D. H. Gutmann, unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

The Neurofibromatosis 2 Protein, Merlin, Regulates Glial Cell Growth in an ErbB2- and Src-Dependent Manner

Houshmandi

Emnett

Giovannini

et al. 2009

Molecular and Cellular Biology

View full text Add to dashboard Cite

Individuals with the inherited cancer predisposition syndrome neurofibromatosis 2 (NF2) develop several central nervous system (CNS) malignancies, including glial cell neoplasms (ependymomas). Recent studies have suggested that the NF2 protein, merlin (or schwannomin), may regulate receptor tyrosine kinase signaling, intracellular mitogenic growth control pathways, or adherens junction organization in non-nervous-system cell types. For this report, we used glial fibrillary acidic protein conditional knockout mice and derivative glia to determine how merlin regulates CNS glial cell proliferation. We show that the loss of merlin in glial cells results in increased proliferation in vitro and in vivo. Merlin regulation of glial cell growth reflects deregulated Src activity, such that pharmacologic or genetic inhibition of Src activation reduces Nf2 ؊/؊ glial cell growth to wild-type levels. We further show that Src regulates Nf2؊/؊ glial cell growth by sequentially regulating FAK and paxillin phosphorylation/activity. Next, we demonstrate that Src activation results from merlin regulation of ErbB2 activation and that genetic or pharmacologic ErbB2 inhibition reduces Nf2 ؊/؊ glial cell Src/Src effector activation and proliferation to wild-type levels. Lastly, we show that merlin competes with Src for direct binding to ErbB2 and present a novel molecular mechanism for merlin regulation of ErbB2-dependent Src signaling and growth control.Neurofibromatosis type 2 (NF2) is an autosomal dominant inherited cancer syndrome in which affected individuals develop nervous system tumors, including peripheral nerve tumors (schwannomas), leptomeningeal tumors (meningiomas), and glial fibrillary acidic protein (GFAP)-immunoreactive glial cell tumors (spinal ependymomas). NF2 results from a germ line mutation in the NF2 tumor suppressor gene, located on chromosome 22q (46, 60). Tumors in this disorder arise following somatic inactivation of the one remaining wild-type (WT) NF2 allele in specific cell types. In this regard, NF2-associated schwannomas, meningiomas, and ependymomas all exhibit biallelic NF2 gene inactivation (33,47,61). In addition, NF2 gene inactivation is also observed in 50 to 78% of sporadic schwannomas, 32 to 84% of sporadic meningiomas, and 37% of sporadic ependymomas (21, 29), suggesting that this gene is also a key growth regulator in nonhereditary nervous system cancers.The NF2 gene was identified in 1993 and found to code for a 595-amino-acid protein, termed merlin or schwannomin (46, 60). Analysis of the predicted protein sequence revealed striking sequence similarity between merlin and a family of protein 4.1 family members that link the actin cytoskeleton to cell surface glycoproteins (55). In particular, merlin most closely resembles the ezrin/radixin/moesin (ERM) subfamily and has been shown to bind actin as well as to associate with several cell surface glycoproteins, including CD44 and ␤1-integrin (5, 32, 48). However, unlike the ERM proteins, merlin is unique in its capacity to function as a nervous s...

show abstract

“…Construction of recombinant adenoviruses The p27 KIP1 -expressing adenovirus Ad-p27 was constructed and validated according to standard techniques as previously described [17] . In brief, primers were designed according to the full-length human p27 KIP1 cDNA sequence (Genbank Accession, NM 004064.2).…”

Section: Methodsmentioning

confidence: 99%

Adenovirus-mediated delivery of p27KIP1 to prevent wound healing after experimental glaucoma filtration surgery

et al. 2009

View full text Add to dashboard Cite

Aim:The aim of the study was to evaluate the outcome of adenovirus-mediated p27 KIP1 (Ad-p27) expression on wound healing after filtration surgery and to investigate the inhibition of cell proliferation induced by Ad-p27. Methods: We constructed the adenovirus recombinant vector Ad-p27 and administered it to a rabbit model of glaucoma filtration surgery by subconjunctival injection; phosphate-buffered saline (PBS) and mitomycin C (MMC) were used as controls. Intraocular pressure (IOP), bleb scores, and anterior chamber depths were observed during a 28-d period. Histological examinations, fluorescence observations and Western blot analyses were evaluated. Results: Ad-p27 enhanced the surgical outcome and inhibited cell proliferation when compared with PBS. Bleb scores in the Ad-p27-treated eyes were higher than those in the PBS-treated eyes on d 7 (P<0.01), 14 (P<0.01) and 21 (P<0.05). On d 28, IOP remained significantly decreased in the Ad-p27 group compared with the PBS group (P<0.05). However, no differences in bleb scores or IOPs were observed between the Ad-p27 and MMC groups. Histological analysis showed that total cell numbers were markedly reduced, and less scar tissue was observed at the surgical site in eyes treated with Ad-p27. The number of fibroblasts was decreased in Tenon's capsule in Ad-p27-treated eyes; however, a marked and diffuse signal from the green fluorescent protein (GFP) was observed in fibroblasts. Western blot analysis revealed a high level of p27 KIP1 expression in conjunctival epithelium (P<0.01), relatively high expression in superficial scleral stroma (P<0.01), and low expression in corneal epithelium in the Ad-p27 group. Conclusions: Ad-p27 administration significantly improves the outcome of filtration surgery and inhibits postoperative proliferation in rabbit eyes. These findings suggest that p27 KIP1 is a potential adjunctive agent for inhibition of wound healing after filtration surgery.

show abstract

Focal Adhesion Kinase Controls Cellular Levels of p27/Kip1 and p21/Cip1 through Skp2-Dependent and -Independent Mechanisms

Cited by 65 publications

References 83 publications

Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice

Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice

The Neurofibromatosis 2 Protein, Merlin, Regulates Glial Cell Growth in an ErbB2- and Src-Dependent Manner

Adenovirus-mediated delivery of p27KIP1 to prevent wound healing after experimental glaucoma filtration surgery

Contact Info

Product

Resources

About