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The '''CIP/KIP''' (CDK interacting protein/Kinase inhibitory protein) family is one of two families (CIP/KIP and [[INK4]]) of mammalian cyclin dependent kinase ([[Cyclin-dependent kinase|CDK]]) inhibitors ([[Cyclin-dependent kinase inhibitor protein|CKIs]]) involved in regulating the cell cycle.<ref name=Morgan2007>{{cite book |vauthors=Morgan DO |title=The Cell Cycle: Principles of Control |publisher=Primers in Biology |year=2007}}</ref><ref name=Sherr1999>{{cite journal |vauthors=Sherr CJ, Roberts JM |title=CDK inhibitors: positive and negative regulators of G1-phase progression |journal=Genes & Development |volume=13 |issue=12 |pages=1501–1512 |year=1999|doi=10.1101/gad.13.12.1501 |pmid=10385618 |doi-access=free }}</ref>  The CIP/KIP family is made up of three proteins: [[p21 | p21<sup>cip1/waf1</sup>]],<ref name=Gu1993>{{cite journal |vauthors=Gu Y, Turek CW, Morgan DO |title=Inhibition of CDK 2 activity in vivo by an associated 20K regulatory subunit |journal=Nature |volume=366 |issue=6456 |pages=707–710 |year=1993|doi=10.1038/366707a0 |pmid=8259216 |bibcode=1993Natur.366..707G |s2cid=4368793 }}</ref><ref name=Xiong1993>{{cite journal |vauthors=Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D |title=p21 is a universal inhibitor of cyclin kinases |journal=Nature |volume=366 |issue=6456 |pages=701–704 |year=1993|doi=10.1038/366701a0 |pmid=8259214 |bibcode=1993Natur.366..701X |s2cid=4362507 }}</ref> [[CDKN1B|P27<sup>kip1</sup>]],<ref name=Toyoshima1994>{{cite journal |vauthors=Toyoshima H, Hunter T |title=p27, a novel inhibitor of G1 cyclin/cdk protein kinase activity, is related to p21 |journal=Cell |volume=78 |issue=1 |pages=67–74 |year=1994|doi=10.1016/0092-8674(94)90573-8 |pmid=8033213 |s2cid=39776582 }}</ref>  [[Cyclin-dependent kinase inhibitor 1C|p57<sup>kip2</sup>]]<ref name=Matsuoka1995>{{cite journal |vauthors=Matsuoka S, Edwards M, Bai C, Parker S, Zhang P, Baldini A, Harper JW, Elledge SJ |title=p57kip2, a structureally distinct member of the p21 cip1 cdk inhibitor family, is a candidate tumor suppressor gene |journal=Genes & Development |volume=9 |issue=6 |pages=650–662 |year=1995|doi=10.1101/gad.9.6.650 |pmid=7729684 |doi-access=free }}</ref><ref name=Lee1995>{{cite journal |vauthors=Lee MH, Reynisdottir I, Massague J |title=Cloning of p57kip2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution |journal=Genes & Development |volume=9 |issue=6 |pages=639–649 |year=1995|doi=10.1101/gad.9.6.639 |pmid=7729683 |doi-access=free }}</ref>   These proteins share sequence homology at the N-terminal domain which allows them to bind to both the [[cyclin]] and [[Cyclin-dependent kinase|CDK]]. Their activity primarily involves the binding and inhibition of G1/S- and S-Cdks; however, they have also been shown to play an important role in activating the G1-CDKs [[Cyclin-dependent kinase 4|CDK4]] and [[Cyclin-dependent kinase 4|CDK6]].<ref name=Soos1996>{{cite journal |vauthors=Soos TJ, Kiyokawa H, Yan JS, Rubin MS, Giordano A, DeBlasio A, Bottega S, Wong B, Mendelsohn J, Koff A |title=Formation of p27-CDK complexes during the human mitotic cell cycle |journal=Cell Growth & Differentiation |volume=7 |pages=135–146 |year=1996}}</ref><ref name=LeBaer1997>{{cite journal |vauthors=LeBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A, Harlow E |title=New functional activities for the p21 family of CDK inhibitors |journal=Genes & Development |volume=11 |issue=7 |pages=847–862 |year=1997|doi=10.1101/gad.11.7.847 |pmid=9106657 |doi-access=free }}</ref>  In addition, more recent work has shown that CIP/KIP family members have a number of CDK-independent roles involving regulation of [[Transcription (biology)|transcription]], [[apoptosis]], and the [[cytoskeleton]].<ref name=Coqueret2003>{{cite journal |vauthors=Coqueret O |title=New roles for p21 and p27 cell-cycle inhibitors: A function for each cell compartment? |journal=Trends in Cell Biology |volume=13 |issue=2 |pages=65–70 |year=2003|doi=10.1016/S0962-8924(02)00043-0 |pmid=12559756 }}</ref><ref name=Nagahara1998>{{cite journal |vauthors=Nagahara H, Vocero-Akbani AM, Snyder EL, Ho A, Latham DG, Lissy NA, Becker-Hapak M, Ezhevsky SA, Dowdy SF |title= Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration |journal=Nature Methods |volume=4 |pages=1449–1452 |year=1998 |issue= 12 |doi=10.1038/4042|pmid= 9846587 |s2cid= 10962704 }}</ref><ref name=Besson2004>{{cite journal |vauthors=Besson A, Gurian-West M, Schmidt A, Hall A, Roberts JM |title= p27Kip1 modulates cell migration through the regulation of RhoA activation |journal=Genes & Development |volume=18 |issue= 8 |pages=851–855 |year=2004|doi= 10.1101/gad.1185504 |pmid= 15078817 |pmc= 395846 }}</ref><ref name=Wang1997>{{cite journal |vauthors=Wang YA, Elson A, Leder P |title= Loss of p21 increases sensitivity to ionizing radiation and delays the onset of lymphoma in atm-deficient mice. |journal=PNAS |volume=94 |issue= 26 |pages=14590–14595 |year=1997|doi= 10.1073/pnas.94.26.14590 |pmid= 9405657 |pmc= 25064 |bibcode= 1997PNAS...9414590W |doi-access= free }}</ref>
==Role in cell cycle progression==
CIP/KIP family proteins bind a wide range of G1/S and S-phase cyclin-CDK complexes including [[Cyclin D/Cdk4|cyclin D-CDK4,6]] and cyclin E-, A-CDK2 complexes.  Traditionally it was assumed that CIP/KIP proteins played a role in inhibiting all of these complexes; however it was later discovered that CIP/KIP proteins, while inhibiting [[Cyclin-dependent kinase 2|CDK2]] activity, may also activate cyclin D-CDK4,6 activity by facilitating stable binding between cyclin D and CDK4,6.
===cyclinA-CDK2 regulation===
The crystal structure of p27 in a complex with cyclinA-CDK2 was published in 1996.<ref name=Russo1996>{{cite journal |vauthors=Russo AA, Jeffrey PD, Patten AK, Massague J, Pavletich NP |title= Crystal structure of the p27Kip1 cyclin-dependent kinase inhibitor bound to the cyclin A-cdk2 complex. |journal=Nature |volume=382 |issue= 6589 |pages=325–331 |year=1996|doi= 10.1038/382325a0 |pmid= 8684460 |bibcode= 1996Natur.382..325R |s2cid= 4284942 }}</ref> The structure shows that p27 interacts with both cyclin A and CDK2.  In addition, p27 mimics ATP and inserts itself into the ATP binding site thus preventing ATP binding.  This mechanism blocks any kinase activity and prevents downstream hyper-phosphorylation of [[Retinoblastoma protein|Rb]] that allows release of the [[E2F]] transcription factor and transcription of cell cycle-related genes.
===cyclinD-CDK4,6 regulation===
Cyclin D has low affinity for its CDK.  Therefore, it was hypothesized that additional proteins were needed to allow for a stable cyclin D-CDK4,6 complex. Growing evidence has shown that CIP/KIP proteins are involved in this stabilization.  The first evidence of this came from the observation that p27 would frequently immunoprecipitate with active cyclin D-CDK4 complexes.  Futhurmore, mouse embryonic fibroblasts deficient for p21 and p27 had lower levels of cyclin D1 and immunoprecipitated cyclinD-CDK complexes had no kinase activity.<ref name="Soos1996"/><ref name="LeBaer1997"/>  These effects were rescued with reintroduction of p21 and p27, but not reintroduction of cyclin D1 suggesting that CIP/KIP proteins are crucial for cyclin D-CDK activity.<ref name=Cheng1999>{{cite journal |vauthors=Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM, Sherr CJ |title=The p21Cip1 and p27Kip1 CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts |journal=EMBO Journal  |volume=18 |issue=6 |pages=1571–1583 |year=1999 |doi=10.1093/emboj/18.6.1571|pmid=10075928 |pmc=1171245 }}</ref> In vitro evidence has shown that cyclin D-CDK binding of CIP/KIP is not restricted to p21 and p27 and can also be performed by p57.<ref name="LeBaer1997"/>
===Model of CIP/KIP G1-S regulation===
The divergent role of CIP/KIP proteins based on whether they are bound to CDK2 or CDK4,6 has led to a model whereby CIP/KIP proteins bind to and inactivate CDK2 complexes in early G1; however, following production of Cyclin D, CIP/KIP proteins are removed and repurposed towards cyclin D-CDK stabilization.  This sequestering then frees up Cyclin A-, E-CDK2 to hyperphosphorylate Rb and promote progression of the cell cycle.  This model is supported by the finding that expression of either wild-type or catalytically inactive CDK4 can sequester CIP/KIP proteins resulting in cyclin E-CDK2 activation. This finding suggests that the ability of cyclinD-CDK complexes to sequester CIP/KIP proteins is predominates their inhibitory activity of CDK2.<ref name="Morgan2007"/><ref name="Sherr1999"/><ref name=Jiang1998>{{cite journal |vauthors=Jiang H, Chou HS, Zhu L |title=Requirement of cyclin E-cdk2 inhibition in p16INK4a-mediated growth suppression |journal=Molecular and Cellular Biology |volume=18 |issue=9 |pages=5284–5290 |year=1998|doi=10.1128/MCB.18.9.5284 |pmid=9710613 |pmc=109114 }}</ref>
==Roles outside of cell cycle progression==
===Apoptosis===
CIP/KIP proteins have been shown to regulate [[apoptosis]] via a variety of mechanisms. p21 and p27 cleavage are known to promote apoptosis through activation of CDK2 activation.<ref name=Levkau1998>{{cite journal |vauthors=Levkau B, Koyama H, Raines EW, Clurman BE, Herren B, Orth K, Roberts JM, Ross R |title=Cleavage of p21Cip?Waf1 and P27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade |journal=Molecular Cell |volume=1 |issue=4 |pages=553–563 |year=1998|doi=10.1016/S1097-2765(00)80055-6 |pmid=9660939 |doi-access=free }}</ref> p57 has also been shown to inhibit apoptosis as p57 null mice show a range of developmental defects including cleft palate and a range of intestinal abnormalities associated with increased apoptosis.<ref name=Yan1997>{{cite journal |vauthors=Yan Y, Frisen J, Lee MH, Massague J, Barbacid M |title= Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development. |journal=Genes & Development |volume=11 |issue= 8 |pages=973–983 |year=1997|doi= 10.1101/gad.11.8.973 |pmid= 9136926 |doi-access=free }}</ref>
CIP/KIP proteins have also been shown to regulate apoptosis via CDK-independent mechanisms. p57 can bind [[MAPK8|JNK1/SAPK]], a stress-related kinase, and block its activity, protecting against JNK1-regulated apoptosis.<ref name=Chang2003>{{cite journal |vauthors=Chang TS, Kim MJ, Ryoo K, Park J, Eom SJ, Shim J, Nakayama KI, Nakayama K, Tomita M, Takahashi K, et al |title= p57Kip2 modulates stress-activated signaling by inhibiting c-Jun NH2-terminal kinase/stress-activated protein kinase. |journal=Journal of Biological Chemistry |volume=278 |issue= 48 |pages=1158–1164 |year=2003|doi= 10.1074/jbc.M309421200 |pmid= 12963725 |doi-access=free }}</ref>
===Transcription===
CIP/KIP proteins can regulate transcription indirectly through stabilization of cyclinD-CDK and uninhibiting cyclin-CDK2 complexes that are crucial for Rb phosphorylation and release of the E2F transcription factor.  CIP/KIP proteins have also been shown to directly bind transcription factors. For example. p27 has been shown to bind to and stabilize [[Neurogenin-2]] promoting differentiation of neural progenitor cells.<ref name=Nguyen2006>{{cite journal |vauthors=Nguyen L, Besson A, Heng J, Schurrmans C, Teboul L, Philpott A, Roberts JM, Guillemot F |title= P27Kip1 independently promotes neuronal differentiation and migration in the cerebral cortex |journal=Genes & Development |volume=20 |issue= 11 |pages=1511–1524|year=2006|doi= 10.1101/gad.377106 |pmid= 16705040 |pmc= 1475763 }}</ref>
===Cytoskeleton===
CIP/KIP proteins have previously been shown to inhibit [[RHOA|Rho]]/[[ROCK1|ROCK]]/LIMK/[[Cofilin]] signaling.<ref name="Besson2004"/>  In addition, fibroblasts deficient for p27 have reduced motility.<ref name=McAllister2003>{{cite journal |vauthors=McAllister SS, Becker-Hapak M, Pintucci G, Pagano M, Dowdy SF |title= Novel p27(kip1) C-terminal scatter domain mediates Rac-dependent cell migration independent of cell cycle arrest functions. |journal=Molecular and Cellular Biology |volume=23 |issue= 1 |pages=216–228 |year=2003|doi= 10.1128/MCB.23.1.216-228.2003 |pmid= 12482975 |pmc= 140659 }}</ref>  p27 deficient fibroblasts also have increased levels of stress fibers and focal adhesions.<ref name="Besson2004"/>  The role of CIP/KIP proteins in motility has also become particularly of interest in cancer where misregulation of p27 could result in increased proliferation and increased motility which may contribute to more invasive cancers.
==Role in cancer and disease==
As cyclin-dependent kinase inhibitors, CIP/KIP proteins have been classically viewed as [[Tumor suppressor gene|tumor suppressors]]; however, the exact role of CIP/KIP proteins in cancer progression has been difficult to assess because a complete loss of CIP/KIP function has not been observed in any cancers.<ref name="Sherr1999"/>  However, low-expression p27 has been observed in a wide variety of tumors and is associated with increased tumor aggression.<ref name=Catzavelos1997>{{cite journal |vauthors=Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, Shaw P, Yeger H, Morava-Protzner I, Kapusta L, Franssen E, Pritchard KI, Slingerland JM |title=Decreased levels of the cell-cycle inhibitor p27Kip1 protein: Prognostic implications in primary breast cancer |journal=Nature Medicine |volume=3 |issue=2 |pages=227–230 |year=1997|doi=10.1038/nm0297-227 |pmid=9018244 |s2cid=25460889 }}</ref><ref name=Loda1997>{{cite journal |vauthors=Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, Jessup JM, Pagano M |title=Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas |journal=Nature Medicine |volume=3 |issue=2 |pages=231–234 |year=1997|doi=10.1038/nm0297-231 |pmid=9018245 |s2cid=3164478 }}</ref> In addition, p27 null mice spontaneously develop tumors in the pituitary gland and are more susceptible to chemical carcinogens or irradiation.<ref name="Nakayama1996">{{cite journal |vauthors=Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I, Loh DY, Nakayama K |title=Mice lacking p27Kip1 display increased body size, multiple organ hyperplasia, retinal dysplasia and pituitary tumors |journal=Cell |volume=85 |issue=5 |pages=701–720 |year=1996|doi=10.1016/S0092-8674(00)81237-4 |pmid=8646779 |s2cid=2009281 |doi-access=free }}</ref><ref name="Fero1996">{{cite journal |vauthors=Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Poyak K, Tsai LH, Broudy V, Perlmutter RM, et al |title=A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice |journal=Cell |volume=85 |issue=5 |pages=733–744 |year=1996|doi=10.1016/S0092-8674(00)81239-8 |pmid=8646781 |s2cid=15490866 |doi-access=free }}</ref><ref name="Fero1998">{{cite journal |vauthors=Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ |title=The murine gene p27Kip1 is haplo-insufficient for tumour suppression. |journal=Nature |volume=396 |issue=6707 |pages=177–180 |year=1998|doi=10.1038/24179 |pmid=9823898 |pmc=5395202 |bibcode=1998Natur.396..177F }}</ref>  In particular, not only the expression of p27, but also the subcellular localization of p27 is thought to play an important role in tumorigenesis.<ref name=Besson2004b>{{cite journal |vauthors=Besson A, Assoian RK, Roberts JM |title= Regulation of the cytoskeleton: an oncogenic function for CDK inhibitors? |journal=Nature Reviews Cancer |volume=4 |issue= 12 |pages=948–955 |year=2004|doi= 10.1038/nrc1501 |pmid= 15573116 |s2cid= 12663308 }}</ref>  Elevated cytoplasmic localization of p27 has been observed in a number of cancers and has been associated with a poor prognosis.  This mislocalization could potentially explain how p27 could simultaneously promote cell cycle progression and increased motility in cancers. A similar model could also be equally true of other CIP/KIP proteins.<ref name="Besson2004b"/><ref name="Blain2003">{{cite journal |vauthors=Blain SW, Scher HI, Cordon-Cardo C, Koff A |title= p27 as a target for cancer therapeutics |journal=Cancer Cell |volume=3 |issue= 2 |pages=111–115 |year=2003|doi= 10.1016/S1535-6108(03)00026-6 |pmid=12620406 |doi-access=free }}</ref><ref name=Denicourt2007>{{cite journal |vauthors=Denicourt C, Saenz CC, Datnow B, Cui XS, Dowdy SF |title= Relocalized p27Kip1 tumor suppressor functions as a cytoplasmic metastatic oncogene in melanoma |journal=Cancer Research |volume=67 |issue= 19 |pages=9238–9243 |year=2007|doi= 10.1158/0008-5472.CAN-07-1375 |pmid= 17909030 |doi-access=free }}</ref><ref name=Slingerland2000>{{cite journal |vauthors=Slingerland J, Pagano MA |title= Regulation of the CDK inhibitor p27 and its deregulation in cancer  |journal=Journal of Cellular Physiology |volume=183 |pages=10–17 |year=2000|issue= 1 |doi= 10.1002/(SICI)1097-4652(200004)183:1<10::AID-JCP2>3.0.CO;2-I |pmid= 10699961 |s2cid= 8756686 }}</ref>
==References==
{{Reflist}}
{{DEFAULTSORT:CIP KIP}}
[[Category:Protein families]]
[[Category:Cell cycle]]