Limits...
Efficient Wnt mediated intestinal hyperproliferation requires the cyclin D2-CDK4/6 complex.

Myant K, Sansom O - Cell Div (2011)

Bottom Line: We showed that the hyperproliferative phenotype associated with Apc loss in vivo was partially dependent on the expression of cyclin D2.This commentary discusses the significance of this work in providing evidence for the importance of the cyclin D2-CDK4/6 complex in colorectal adenoma formation.It also argues that inhibition of this complex may be an effective chemopreventative strategy in CRC.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, UK. o.sansom@beatson.gla.ac.uk.

ABSTRACT
Inactivation of the gene encoding the adenomatous polyposis coli (APC) tumour suppressor protein is recognized as the key early event in the development of colorectal cancers (CRC). Apc loss leads to nuclear localization of beta-catenin and constitutive activity of the beta-catenin-Tcf4 transcription complex. This complex drives the expression of genes involved in cell cycle progression such as c-Myc and cyclin D2. Acute loss of Apc in the small intestine leads to hyperproliferation within the intestinal crypt, increased levels of apoptosis, and perturbed differentiation and migration. It has been demonstrated that c-Myc is a critical mediator of the phenotypic abnormalities that follow Apc loss in the intestine. As it may be difficult to pharmacologically inhibit transcription factors such as c-Myc, investigating more druggable targets of the Wnt-c-Myc pathway within the intestine may reveal potential therapeutic targets for CRC. Recent work in our laboratory has shown that the cyclin D2-cyclin-dependent kinase 4/6 (CDK4/6) complex promotes hyperproliferation in Apc deficient intestinal tissue and ApcMin/+ adenomas. We showed that the hyperproliferative phenotype associated with Apc loss in vivo was partially dependent on the expression of cyclin D2. Most importantly, tumour growth and development in ApcMin/+ mice was strongly perturbed in mice lacking cyclin D2. Furthermore, pharmacological inhibition of CDK4/6 suppressed the proliferation of adenomatous cells. This commentary discusses the significance of this work in providing evidence for the importance of the cyclin D2-CDK4/6 complex in colorectal adenoma formation. It also argues that inhibition of this complex may be an effective chemopreventative strategy in CRC.

No MeSH data available.


Related in: MedlinePlus

Cyclin D2-CDK4/6 complex drives efficient hyperproliferation in Apc deficient cells. (A) In the normal intestinal epithelium Wnt activity and hence c-Myc levels are restricted. This prevents accumulation of the cyclin D2-CDK4/6 complex and suppresses proliferation. (B) In Apc deficient cells Wnt activity and c-Myc levels are high. The high levels of c-Myc lead to accumulation of cyclin D2 and CDK4/6, possibly via their direct transcriptional activation. The complex of cyclin D2 and CDK4/6 phosphorylates Rb and permits E2F to drive cell cycle entry and subsequent hyperproliferation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3040687&req=5

Figure 1: Cyclin D2-CDK4/6 complex drives efficient hyperproliferation in Apc deficient cells. (A) In the normal intestinal epithelium Wnt activity and hence c-Myc levels are restricted. This prevents accumulation of the cyclin D2-CDK4/6 complex and suppresses proliferation. (B) In Apc deficient cells Wnt activity and c-Myc levels are high. The high levels of c-Myc lead to accumulation of cyclin D2 and CDK4/6, possibly via their direct transcriptional activation. The complex of cyclin D2 and CDK4/6 phosphorylates Rb and permits E2F to drive cell cycle entry and subsequent hyperproliferation.

Mentions: In conclusion, our study has provided important in vivo evidence of an essential role for the cyclin D2-CDK4/6 complex in efficient hyperproliferation in tumour cells where Wnt is activated (Figure 1). We would therefore argue that the use of CDK4/6 inhibitors such as PD0332991 warrants further investigation in murine models of CRC.


Efficient Wnt mediated intestinal hyperproliferation requires the cyclin D2-CDK4/6 complex.

Myant K, Sansom O - Cell Div (2011)

Cyclin D2-CDK4/6 complex drives efficient hyperproliferation in Apc deficient cells. (A) In the normal intestinal epithelium Wnt activity and hence c-Myc levels are restricted. This prevents accumulation of the cyclin D2-CDK4/6 complex and suppresses proliferation. (B) In Apc deficient cells Wnt activity and c-Myc levels are high. The high levels of c-Myc lead to accumulation of cyclin D2 and CDK4/6, possibly via their direct transcriptional activation. The complex of cyclin D2 and CDK4/6 phosphorylates Rb and permits E2F to drive cell cycle entry and subsequent hyperproliferation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3040687&req=5

Figure 1: Cyclin D2-CDK4/6 complex drives efficient hyperproliferation in Apc deficient cells. (A) In the normal intestinal epithelium Wnt activity and hence c-Myc levels are restricted. This prevents accumulation of the cyclin D2-CDK4/6 complex and suppresses proliferation. (B) In Apc deficient cells Wnt activity and c-Myc levels are high. The high levels of c-Myc lead to accumulation of cyclin D2 and CDK4/6, possibly via their direct transcriptional activation. The complex of cyclin D2 and CDK4/6 phosphorylates Rb and permits E2F to drive cell cycle entry and subsequent hyperproliferation.
Mentions: In conclusion, our study has provided important in vivo evidence of an essential role for the cyclin D2-CDK4/6 complex in efficient hyperproliferation in tumour cells where Wnt is activated (Figure 1). We would therefore argue that the use of CDK4/6 inhibitors such as PD0332991 warrants further investigation in murine models of CRC.

Bottom Line: We showed that the hyperproliferative phenotype associated with Apc loss in vivo was partially dependent on the expression of cyclin D2.This commentary discusses the significance of this work in providing evidence for the importance of the cyclin D2-CDK4/6 complex in colorectal adenoma formation.It also argues that inhibition of this complex may be an effective chemopreventative strategy in CRC.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, UK. o.sansom@beatson.gla.ac.uk.

ABSTRACT
Inactivation of the gene encoding the adenomatous polyposis coli (APC) tumour suppressor protein is recognized as the key early event in the development of colorectal cancers (CRC). Apc loss leads to nuclear localization of beta-catenin and constitutive activity of the beta-catenin-Tcf4 transcription complex. This complex drives the expression of genes involved in cell cycle progression such as c-Myc and cyclin D2. Acute loss of Apc in the small intestine leads to hyperproliferation within the intestinal crypt, increased levels of apoptosis, and perturbed differentiation and migration. It has been demonstrated that c-Myc is a critical mediator of the phenotypic abnormalities that follow Apc loss in the intestine. As it may be difficult to pharmacologically inhibit transcription factors such as c-Myc, investigating more druggable targets of the Wnt-c-Myc pathway within the intestine may reveal potential therapeutic targets for CRC. Recent work in our laboratory has shown that the cyclin D2-cyclin-dependent kinase 4/6 (CDK4/6) complex promotes hyperproliferation in Apc deficient intestinal tissue and ApcMin/+ adenomas. We showed that the hyperproliferative phenotype associated with Apc loss in vivo was partially dependent on the expression of cyclin D2. Most importantly, tumour growth and development in ApcMin/+ mice was strongly perturbed in mice lacking cyclin D2. Furthermore, pharmacological inhibition of CDK4/6 suppressed the proliferation of adenomatous cells. This commentary discusses the significance of this work in providing evidence for the importance of the cyclin D2-CDK4/6 complex in colorectal adenoma formation. It also argues that inhibition of this complex may be an effective chemopreventative strategy in CRC.

No MeSH data available.


Related in: MedlinePlus