# RAC1B: A Rho GTPase with Versatile Functions in Malignant Transformation and Tumor Progression
## 5 Biological Functions of RAC1B
### Cellular Senescence  
Interestingly, it was shown that with the help of RAC1B, cells may be able to overcome OIS. Expression of mouse Rac1b in lung epithelial cells of transgenic mice stimulated EMT and spontaneous tumor development. Through bypassing OIS, MMP-induced Rac1b was able to induce lung adenocarcinoma in the transgenic mice [23].  
Oncogenic B-RAF-V600E expressed in normal NCM460 colonocytes induced a senescent phenotype as evidenced by expression of senescence-associated \(\beta\)-galactosidase (SA-\(\beta\)-gal), the cell cycle inhibitors p14 ARF, p15 INK4B and p21 WAF1, and decreased proliferation. Upon coexpression of RAC1B, but not RAC1, the B-RAF-induced senescence phenotype was reverted and expression of the cell cycle inhibitors downregulated in a ROS-dependent manner. Hence, coexpression of RAC1B counteracts B-RAF-induced senescence, indicating increased RAC1B expression as one potential mechanism by which colorectal tumor cells can escape from OIS [48] (Figure 3).  
In pancreatic cancer cells [35] and normal human mammary epithelial cells (HMEC) [46], RAC1B acts as a negative regulator of the TGF-\(\beta\)1-induced cell cycle inhibitor p21 WAF1 which supports proliferative effects of RAC1B on cell cycle progression (see Section 5.7). More evidence for this was obtained using an aging model of HMEC. A majority of HMEC cultures can spontaneously exit the proliferative cell cycle and enter a senescent growth-arrested phenotype after 15-16 passages (P15/P16) in vitro as demonstrated by upregulation of SA-\(\beta\)-gal and the tumor suppressor and cdk inhibitor p16 INK4A [49; 50; 51]. Autocrine production of TGF-\(\beta\) enhanced the senescent phenotype of HMEC whereby premature senescence is often associated with classical TGF-\(\beta\)-mediated responses like growth inhibition, upregulation of p16 INK4A, p21 WAF1, and production of extracellular matrix (ECM) components [51]. Indeed, senescent HMEC display enhanced activity of TGF-\(\beta\) signaling which is supported by TGF-\(\beta\)-mediated pathways to confer upregulation of SMAD2 and SMAD4, p16 INK4A [52], COLA4A2 [53], MMP2 [54], and uPAR [55]. The induction of these genes in senescent HMEC is paralleled by the observation that an accumulation of aging HMEC is associated with enhanced matrix production [56], a hallmark response to TGF-\(\beta\). In accordance with the promigratory role of TGF-\(\beta\) on mammary epithelial cells, senescent HMEC in P15/P16 but not their juvenile counterparts in P11/P12 exhibit strongly enhanced chemokinesis [46]. These findings are paralleled by lower expression of RAC1B and higher expression of RAC1 in the motile high-passage senescent HMEC [46], substantiating inverse regulatory interactions between TGF-\(\beta\) signaling and RAC1B expression. Consequently, RAC1B appears to function as an inhibitor of both TGF-\(\beta\)-dependent migration and TGF-\(\beta\)-induced growth arrest with subsequent induction of senescence. While TGF-\(\beta\) can relay Ras-mediated senescence in HMEC thus preventing malignant transformation [57], it appears conceivable that elevated RAC1B expression allows for an escape from tumor-suppressive senescence and progression towards neoplastic development even in the absence of oncogene activation. Together, the senescence-like growth arrest and cell migration in mammary epithelial cells may be controlled at least in part by RAC1B through its inhibitory effect on the RAS-RAF-MEK-ERK pathway [35] and the TGF-\(\beta\)/SMAD pathway [40] (Figure 3).  
Figure 3: Mechanisms utilized by RAC1B to drive G1/S progression.