SV40 small T antigen and PP2A phosphatase in cell transformation

Sablina, Anna; Hahn, William C.

doi:10.1007/s10555-008-9116-0

Cited by 83 publications

(102 citation statements)

References 113 publications

(149 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…26 Gain of function of the former or loss of function of the latter is commonly found in human cancers, leading in turn to pRb hyperphosphorylation, and its consequential functional inactivation. 27,28 The sequence of molecular events that triggers pRb phosphorylation during early, mid, and late G1 is not well known. By investigating the cofactors that regulate this process, we propose a new model for pRb phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

et al. 2012

View full text Add to dashboard Cite

Inactivation of the retinoblastoma protein (pRb) by phosphorylation triggers uncontrolled cell proliferation. Accordingly, activation of cyclin-dependent kinase (CDK)/cyclin complexes or downregulation of CDK inhibitors appears as a common event in human cancer. Here we show that Pin1 (protein interacting with NIMA (never in mitosis A)-1), a peptidylprolyl isomerase involved in the control of protein phosphorylation, is an essential mediator for inactivation of the pRb. Our results indicate that Pin1 controls cell proliferation by altering pRb phosphorylation without affecting CDK and protein phosphatase 1 and 2 activity. We demonstrated that Pin1 regulates tumor cell proliferation through direct interaction with the spacer domain of the pRb protein, and allows the interaction between CDK/cyclin complexes and pRb in mid/late G1. Phosphorylation of pRb Ser 608/612 is the crucial motif for Pin1 binding. We propose that Pin1 selectively boosts the switch from hypo-to hyper-phosphorylation of pRb in tumor cells. In addition, we demonstrate that the CDK pathway is responsible for the interaction of Pin1 and pRb. Prospectively, our findings therefore suggest that the synergism among CDK and Pin1 inhibitors holds great promise for targeted pharmacological treatment of cancer patients, with the possibility of reaching high effectiveness at tolerated doses. The retinoblastoma protein (pRb), the product of the RB1 gene (i.e., the tumor-suppressor gene involved in hereditary and sporadic retinoblastoma pathogenesis), is mainly responsible for the control of cell proliferation via two different mechanisms. The first is based on the interaction between pRb and different chromatin-modifying enzymes: pRb interacts with histone deacetylases (HDACs) 1, 2, and 3, histone methylase SUV39H1, and chromatin-remodeling enzymes Brg1 and Brm, thus repressing gene expression. 1 The second mechanism involves pRb controlling the cell cycle through interaction with the E2F family of transcription factors 2 in a phosphorylation-dependent way: in early and mid G1, the protein complex D-type cyclins/CDK4, 6 whereas in late G1, cyclins E(A)/CDK2 gradually phosphorylate pRb. Hyperphosphorylated pRb releases E2F transcription factors and allows the expression of genes that mediate entry into the S phase. 3 As pRb protein holds a central role in the cell cycle, its inactivation is necessary for enabling cancer cell proliferation. Different mechanisms of pRb inactivation have been described, although inactivation through phosphorylation is most common in human sporadic cancers. In this context, cyclin D1 overexpression induces CDK4/6 activation and thus pRb hyperphosphorylation. 4,5 In addition, the cyclindependent kinase (CDK) inhibitory partner, p16 protein (i.e.,

show abstract

Section: Discussionmentioning

confidence: 99%

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

et al. 2012

View full text Add to dashboard Cite

show abstract

“…The viral oncoproteins SV40 ST has been demonstrated to perturb critical host cell pathways, facilitating the miR-27a mediates SV40 ST-induced cell transformation Q Wang et al experimental transformation of mammalian cells (Sontag and Sontag, 2006;Sablina and Hahn, 2008). The study of SV40-induced transformation in human cell culture models has promoted the identification of pathways related to cancer development.…”

Section: Discussionmentioning

confidence: 99%

“…These biological functions are believed to be mediated by the interaction between ST and PP2A (reviewed in Arroyo and Hahn, 2005;Eichhorn et al, 2009). The alteration of the phosphorylation status of signaling molecules has been demonstrated to be the primary action of the ST antigen in cell transformation (Janssens and Goris, 2001; Moreno Sablina and Hahn, 2008). Indeed, PP2A complexes formed by various B subunits confer specificity of substrates dephosphorylation (Ferrigno et al, 1993;Cegielska et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Upregulation of miR-27a contributes to the malignant transformation of human bronchial epithelial cells induced by SV40 small T antigen

Wang

et al. 2011

Oncogene

View full text Add to dashboard Cite

“…Human cell transformation requires inhibition of PP2A activity and, in an siRNA screen, B56α, B56γ, and PR72/PR130 were the only B subunits shown to be critical for regulating human cell transformation (14). PP2A complexes containing these B subunits regulate MYC, Wnt, and PI3K/Akt signaling, respectively (9, 14).Whereas loss of PP2A activity is critical for tumor growth, mutations in PP2A subunits are very rare in breast cancers (15,16). Alterations in the A subunit that impair integration of the C and/or B subunits have only been observed in breast cancers at a low frequency (15-18), suggesting that other mechanisms can affect PP2A activity and, subsequently, MYC protein levels.…”

mentioning

confidence: 99%

Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer

Janghorban¹,

Farrell²,

Allen-Petersen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

169

175

View full text Add to dashboard Cite

The transcription factor c-MYC is stabilized and activated by phosphorylation at serine 62 (S62) in breast cancer. Protein phosphatase 2A (PP2A) is a critical negative regulator of c-MYC through its ability to dephosphorylate S62. By inactivating c-MYC and other key signaling pathways, PP2A plays an important tumor suppressor function. Two endogenous inhibitors of PP2A, I2PP2A, Inhibitor-2 of PP2A (SET oncoprotein) and cancerous inhibitor of PP2A (CIP2A), inactivate PP2A and are overexpressed in several tumor types. Here we show that SET is overexpressed in about 50-60% and CIP2A in about 90% of breast cancers. Knockdown of SET or CIP2A reduces the tumorigenic potential of breast cancer cell lines both in vitro and in vivo. Treatment of breast cancer cells in vitro or in vivo with OP449, a novel SET antagonist, also decreases the tumorigenic potential of breast cancer cells and induces apoptosis. We show that this is, at least in part, due to decreased S62 phosphorylation of c-MYC and reduced c-MYC activity and target gene expression. Because of the ubiquitous expression and tumor suppressor activity of PP2A in cells, as well as the critical role of c-MYC in human cancer, we propose that activation of PP2A (here accomplished through antagonizing endogenous inhibitors) could be a novel antitumor strategy to posttranslationally target c-MYC in breast cancer.breast cancer therapy | phosphatase activator T he c-MYC (MYC) oncoprotein is overexpressed in human breast cancer and this is associated with poor clinical outcome (1, 2). Expression of MYC is regulated at multiple levels, including protein stability, which is increased in several cancer types (1,3,4). MYC stability is regulated in part by sequential and interdependent phosphorylation at two conserved residues, threonine 58 (T58) and serine 62 (S62) (5). MYC is phosphorylated at S62 (pS62) through the mitogen-activated protein kinase (MAPK) pathway or cyclin-dependent kinase (CDK) activation in response to growth signals and this modification increases its stability and oncogenic activity (5-8). When growth signals cease, GSK3, in a manner dependent upon prior phosphorylation at S62, phosphorylates T58 (pT58) (5, 6). T58 phosphorylation facilitates protein phosphatase 2A (PP2A)-mediated dephosphorylation of pS62 and recruitment of the E3 ubiquitin ligase SCF Fbw7 to initiate proteasomal destruction of MYC (9, 10). This process is facilitated by AXIN1, which helps nucleate a destruction complex for MYC at target gene promoters (11, 12). Our previous work has shown that MYC stability is increased in breast cancers and that this correlates with high pS62-and low pT58-MYC (4).PP2A is a ubiquitously expressed, heterotrimeric serinethreonine (S/T) phosphatase that mediates 30-50% of cellular S/T phosphatase activity (13). Target specificity of PP2A is directed by a variable regulatory (B) subunit, and we have shown that B56α is the isoform that directs PP2A to MYC (9, 13). Human cell transformation requires inhibition of PP2A activity and, in an siRNA screen, B56α, ...

show abstract

SV40 small T antigen and PP2A phosphatase in cell transformation

Cited by 83 publications

References 113 publications

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

Upregulation of miR-27a contributes to the malignant transformation of human bronchial epithelial cells induced by SV40 small T antigen

Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer

Contact Info

Product

Resources

About