Protein P16
Encyclopedia
The p16 protein is a cyclin-dependent kinase
(CDK) inhibitor that decelerates the cell cycle
by inactivating the CDKs that phosphorylate retinoblastoma protein
(Rb).
(p16) is a cyclin-dependent kinase
(CDK) inhibitor that slows down the progression of the cell cycle
by inactivating the Cyclin dependent kinase
that phosphorylates the retinoblastoma protein
(pRb). Both p16 and retinoblastoma (pRb) are important tumor suppressors that regulate the cell cycle. In addition to protein p16, pRB there are many other important tumor suppressors that regulate the cell cycle and one of them is protein p53
. Cyclin D1
promotes the progression of the cell cycle to the S phase by cyclin D-dependent kinases (CDK4/CDK6). However, the activities of CDK4/CDK6 are restricted by protein p16 since protein p16 is a potent inhibitor of CDKs
. Protein Rb, p16 and cyclin D1 are major restriction factors of the cell cycle restriction check points. The progression of cells from G1 phase
to S phase
is blocked by protein p16, which is a potential tumor suppressor that acts to disrupt the complex cyclin D1 and CDK 4 or 6. The most critical point in cell cycle regulation is the G1 checkpoint and it is at this checkpoint, that the complex cyclin D1 interactions take place to determine whether the cell cycle goes back into a quiescent state (G0) phase
or enter into the S phase, where cells are destined to divide. when cells enter in to the S phase the cells divide uncontrollably and that leads to cancer. It is important to note that Cyclin D1
is not a kinase but it activates kinases and it also appears to be most strongly implicated in human carcinogenesis. When Cyclin D1 interacts with cyclin-dependent kinase-4 or 6 (CDK-4/6), it leads to a conformational change to CDK-4 or 6 however, cyclin D1
does not undergo conformational change. The interaction of cyclin D and CDK4 forms a complex that inactivates the tumor suppressor protein retinoblastoma through phosphorylation. Phosphorylation of pRb releases transcription factors such as E2Fs which then activate a series of events that allow entry into the S-phase and promotes cell division. However, Phosphorylation of pRb leads to a conformational change to E2F
as well. However,protein p15
and protein p16 are inhibit cyclin D1 from binding to the CDKs. Another important Protein tumor suppressor is p21 and what it does is block the CDKs at any point in the cell cycle. Protein p21
is under control of p53
tumor suppressor protein. Some of the biological functions of protein p53 are as a transcriptional factor and also it regulates apoptosis. The stochometric level of protein p53 in the cell is very small because if it is large then it kills the cells. P53
is regulated by MDM2
which regulates the amount of protein or in other words it facilitates degradation in DNA damage checkpoint. Oncogenic ras can transform most immortal cells to a tumorigenic state. However, transformation of primary cells by ras requires either a cooperating oncogene or the inactivation of tumor suppressors such as p53 or p16. Researches show that expression of oncogenic ras in primary human cells results in a permanent G1
arrest and this arrest is by ras and is accompanied by accumulation of p53
and p16
. However, inactivation of either p53 or p16 prevents ras-induced arrest in cells. This suggests that the onset of cellular senescence
does not simply reflect the accumulation of cell divisions, but can be prematurely activated in response to an oncogenic stimulus. It is believed that negation of ras-induced senescence may be relevant during multistep tumorigenesis.
E7 protein. In the case of cervical cancer PRB is functionally inactivated by HPV oncoproteins and that results in p16 overexpression. In addition to that, overexpression of the protein p16 is a useful diagnostic tool for cervical cancer laboratory screening. Many recent and previous immunohistochemical studies have clearly demonstrated that p16 is strongly expressed in almost all cervical cancers. Many people mistakenly take the fact that the low expression of protein p16 in the cell as a free condition of cervical cancer however it is not always true. Protein p16 regulates cell proliferation and pRb acts as a negative regulator of protein p16. It was also shown that p16 is involved in the regulation of the cellular life span and accumulates in senescent cells. Some studies also reported that transcriptional silencing of the p16 promoter by hypermethylation as a dominant mechanism of inactivation of the tumor suppressor in head and neck squamous cell carcinoma. It is believed that excesse of cyclin D and cyclin E
is produced in breast cancer cells. A possible therapy in cancer is to by blocking cyclins and CDK’s activates. the only possible way of inactivating the CDKs is through the inhibitor protein p16. In the p16/cyclin D1/cdk4/pRb cell cycle regulatory cascade, the correlation between pRb and p16 is believed to be obvious in various cancer types. Thus, loss of p16, overexpression of D-cyclins and loss of RB have similar effects on G1 cell cycle progression, and may represent a common pathway to tumorigenesis.
begins when cyclin D
which is a kinase activator binds itself to CDK4/ CDK6. upon the interaction CDK undergoes conformational change
and the complex formed triggers pRB phosphorylation. then, pRB which undergoes conformational change and is now functionally inactivated since its size, shape and charge is different hence it can not fit as before. However, the phosphorylated pRB releases a transcription factor E2F
that causes induction of p16 expression. Then, pl6 proceeds to bind all CDK4/CDK6 hence, cyclin D
is no longer protected by association with its CDK4/CDK6 partner.p16 appears in many pathway mechanisms including DNA damage checkpoint, G1/S checkpoint and many others.
with
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
(CDK) inhibitor that decelerates the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
by inactivating the CDKs that phosphorylate retinoblastoma protein
Retinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...
(Rb).
Function
The proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
(p16) is a cyclin-dependent kinase
Cyclin-dependent kinase
thumb|350px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=Mitosis; G1=[[G1 phase|Gap phase 1]]; S=[[S phase|Synthesis]]; G2=[[G2 phase|Gap phase 2]]...
(CDK) inhibitor that slows down the progression of the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
by inactivating the Cyclin dependent kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
that phosphorylates the retinoblastoma protein
Retinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...
(pRb). Both p16 and retinoblastoma (pRb) are important tumor suppressors that regulate the cell cycle. In addition to protein p16, pRB there are many other important tumor suppressors that regulate the cell cycle and one of them is protein p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
. Cyclin D1
Cyclin D1
G1/S-specific cyclin-D1 is a protein that in humans is encoded by the CCND1 gene.Immunohistochemical staining of cyclin D1 antibodies is used to diagnose mantle cell lymphoma.-Interactions:...
promotes the progression of the cell cycle to the S phase by cyclin D-dependent kinases (CDK4/CDK6). However, the activities of CDK4/CDK6 are restricted by protein p16 since protein p16 is a potent inhibitor of CDKs
Cyclin-dependent kinase
thumb|350px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=Mitosis; G1=[[G1 phase|Gap phase 1]]; S=[[S phase|Synthesis]]; G2=[[G2 phase|Gap phase 2]]...
. Protein Rb, p16 and cyclin D1 are major restriction factors of the cell cycle restriction check points. The progression of cells from G1 phase
G1 phase
The G1 phase is a period in the cell cycle during interphase, before the S phase. For many cells, this phase is the major period of cell growth during its lifespan. During this stage new organelles are being synthesized, so the cell requires both structural proteins and enzymes, resulting in great...
to S phase
S phase
S-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this...
is blocked by protein p16, which is a potential tumor suppressor that acts to disrupt the complex cyclin D1 and CDK 4 or 6. The most critical point in cell cycle regulation is the G1 checkpoint and it is at this checkpoint, that the complex cyclin D1 interactions take place to determine whether the cell cycle goes back into a quiescent state (G0) phase
G0 phase
The G0 phase is a period in the cell cycle in which cells exist in a quiescent state. G0 phase is viewed as either an extended G1 phase, where the cell is neither dividing nor preparing to divide, or a distinct quiescent stage that occurs outside of the cell cycle...
or enter into the S phase, where cells are destined to divide. when cells enter in to the S phase the cells divide uncontrollably and that leads to cancer. It is important to note that Cyclin D1
Cyclin D1
G1/S-specific cyclin-D1 is a protein that in humans is encoded by the CCND1 gene.Immunohistochemical staining of cyclin D1 antibodies is used to diagnose mantle cell lymphoma.-Interactions:...
is not a kinase but it activates kinases and it also appears to be most strongly implicated in human carcinogenesis. When Cyclin D1 interacts with cyclin-dependent kinase-4 or 6 (CDK-4/6), it leads to a conformational change to CDK-4 or 6 however, cyclin D1
Cyclin D1
G1/S-specific cyclin-D1 is a protein that in humans is encoded by the CCND1 gene.Immunohistochemical staining of cyclin D1 antibodies is used to diagnose mantle cell lymphoma.-Interactions:...
does not undergo conformational change. The interaction of cyclin D and CDK4 forms a complex that inactivates the tumor suppressor protein retinoblastoma through phosphorylation. Phosphorylation of pRb releases transcription factors such as E2Fs which then activate a series of events that allow entry into the S-phase and promotes cell division. However, Phosphorylation of pRb leads to a conformational change to E2F
E2F
E2F is a group of genes that codifies a family of transcription factors in higher eukaryotes. Three of them are activators: E2F1, 2 and E2F3a. Six others act as suppressors: E2F3b, E2F4-8. All of them are involved in the cell cycle regulation and synthesis of DNA in mammalian cells...
as well. However,protein p15
CDKN2B
Cyclin-dependent kinase 4 inhibitor B also known as multiple tumor suppressor 2 or p15INK4B is a protein that is encoded by the CDKN2B gene in humans.- Function :...
and protein p16 are inhibit cyclin D1 from binding to the CDKs. Another important Protein tumor suppressor is p21 and what it does is block the CDKs at any point in the cell cycle. Protein p21
P21
p21 / WAF1 also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 is a protein that in humans is encoded by the CDKN1A gene located on chromosome 6 .- Function :...
is under control of p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
tumor suppressor protein. Some of the biological functions of protein p53 are as a transcriptional factor and also it regulates apoptosis. The stochometric level of protein p53 in the cell is very small because if it is large then it kills the cells. P53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
is regulated by MDM2
Mdm2
Mdm2 is an important negative regulator of the p53 tumor suppressor. It is the name of a gene as well as the protein encoded by that gene. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain of the p53 tumor suppressor and an inhibitor of...
which regulates the amount of protein or in other words it facilitates degradation in DNA damage checkpoint. Oncogenic ras can transform most immortal cells to a tumorigenic state. However, transformation of primary cells by ras requires either a cooperating oncogene or the inactivation of tumor suppressors such as p53 or p16. Researches show that expression of oncogenic ras in primary human cells results in a permanent G1
G1
G1, G01, G.I or G-1 can be:-Sports:* G1 Climax, an annual professional wrestling singles tournament held by New Japan Pro Wrestling-Science:* G1 phase in the cellular cycle* G1 regulatory sequence for the insulin gene...
arrest and this arrest is by ras and is accompanied by accumulation of p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
and p16
P16
P16, P-16, or P.6 may refer to:* p16 , also known as p16Ink4A, a gene involved in tumor suppression* AMC Schneider P 16, a French halftrack developed in the 1920s...
. However, inactivation of either p53 or p16 prevents ras-induced arrest in cells. This suggests that the onset of cellular senescence
Senescence
Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
does not simply reflect the accumulation of cell divisions, but can be prematurely activated in response to an oncogenic stimulus. It is believed that negation of ras-induced senescence may be relevant during multistep tumorigenesis.
Clinical Significances
For clinical significances, expression of cyclin D1/p16/pRb play a critical role in tumorigenesis. However, when protein p16 is overexpression it leads to cervical cancer because of the functional inactivation of pRb by human papillomavirusPapillomavirus
Papillomaviridae is an ancient taxonomic family of non-enveloped DNA viruses, collectively known as papillomaviruses. Several hundred species of papillomaviruses, traditionally referred to as "types", have been identified infecting all carefully inspected birds and mammals, but also a small number...
E7 protein. In the case of cervical cancer PRB is functionally inactivated by HPV oncoproteins and that results in p16 overexpression. In addition to that, overexpression of the protein p16 is a useful diagnostic tool for cervical cancer laboratory screening. Many recent and previous immunohistochemical studies have clearly demonstrated that p16 is strongly expressed in almost all cervical cancers. Many people mistakenly take the fact that the low expression of protein p16 in the cell as a free condition of cervical cancer however it is not always true. Protein p16 regulates cell proliferation and pRb acts as a negative regulator of protein p16. It was also shown that p16 is involved in the regulation of the cellular life span and accumulates in senescent cells. Some studies also reported that transcriptional silencing of the p16 promoter by hypermethylation as a dominant mechanism of inactivation of the tumor suppressor in head and neck squamous cell carcinoma. It is believed that excesse of cyclin D and cyclin E
Cyclin E
Cyclin E is a member of the cyclin family.Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase. The Cyclin E/CDK2 complex phosphorylates p27Kip1 , tagging it for degradation, thus promoting expression of Cyclin A, allowing progression to S phase....
is produced in breast cancer cells. A possible therapy in cancer is to by blocking cyclins and CDK’s activates. the only possible way of inactivating the CDKs is through the inhibitor protein p16. In the p16/cyclin D1/cdk4/pRb cell cycle regulatory cascade, the correlation between pRb and p16 is believed to be obvious in various cancer types. Thus, loss of p16, overexpression of D-cyclins and loss of RB have similar effects on G1 cell cycle progression, and may represent a common pathway to tumorigenesis.
Protein p16 Pathway
Protein p16 pathway mechanism in cell cycleCell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
begins when cyclin D
Cyclin D
Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition...
which is a kinase activator binds itself to CDK4/ CDK6. upon the interaction CDK undergoes conformational change
Conformational change
A macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a conformational change...
and the complex formed triggers pRB phosphorylation. then, pRB which undergoes conformational change and is now functionally inactivated since its size, shape and charge is different hence it can not fit as before. However, the phosphorylated pRB releases a transcription factor E2F
E2F
E2F is a group of genes that codifies a family of transcription factors in higher eukaryotes. Three of them are activators: E2F1, 2 and E2F3a. Six others act as suppressors: E2F3b, E2F4-8. All of them are involved in the cell cycle regulation and synthesis of DNA in mammalian cells...
that causes induction of p16 expression. Then, pl6 proceeds to bind all CDK4/CDK6 hence, cyclin D
Cyclin D
Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition...
is no longer protected by association with its CDK4/CDK6 partner.p16 appears in many pathway mechanisms including DNA damage checkpoint, G1/S checkpoint and many others.
Interaction
p16 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with
- SERTAD1SERTAD1SERTA domain-containing protein 1 is a protein that in humans is encoded by the SERTAD1 gene.-Interactions:SERTAD1 has been shown to interact with P16, Cyclin-dependent kinase 4 and CREB-binding protein.-Further reading:...
- CDKCyclin-dependent kinasethumb|350px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=Mitosis; G1=[[G1 phase|Gap phase 1]]; S=[[S phase|Synthesis]]; G2=[[G2 phase|Gap phase 2]]...
- Cyclin D1Cyclin D1G1/S-specific cyclin-D1 is a protein that in humans is encoded by the CCND1 gene.Immunohistochemical staining of cyclin D1 antibodies is used to diagnose mantle cell lymphoma.-Interactions:...
- p53P53p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
- pRBPRBPRB may refer to:* PRB , the Australian Automotive Manufacturer* PRB * The unofficial ISO 4217 code for the Transnistrian rublePRB is short for:* Powder River Basin, a major coal producing geologic basin in the USA...
Further reading
- Smith-Sørensen B, Hovig E (1996). "CDKN2A (p16INK4A) somatic and germline mutations.". Hum. Mutat. 7 (4): 294–303. doi:10.1002/(SICI)1098-1004(1996)7:4<294::AID-HUMU2>3.0.CO;2-9 (inactive 2009-10-08). PMID 8723678
- Gjerset RA (2007). "DNA damage, p14ARF, nucleophosmin (NPM/B23), and cancer.". J. Mol. Histol. 37 (5-7): 239–51. doi:10.1007/s10735-006-9040-y. PMID 16855788
- Akita H (2003). "[Prognostic importance of altered expression of cell cycle regulators in lung cancer]". Nippon Rinsho 60 Suppl 5: 267–71. PMID 12101670
- Marone M, Bonanno G, Rutella S, et al. (2003). "Survival and cell cycle control in early hematopoiesis: role of bcl-2, and the cyclin dependent kinase inhibitors P27 and P21.". Leuk. Lymphoma 43 (1): 51–7. doi:10.1080/10428190210195. PMID 11908736
- Zhang Z, Wang H, Li M, et al. (2006). "Novel MDM2 p53-independent functions identified through RNA silencing technologies.". Ann. N. Y. Acad. Sci. 1058: 205–14. doi:10.1196/annals.1359.030. PMID 16394138
- Tokumoto M, Tsuruya K, Fukuda K, et al. (2003). "Parathyroid cell growth in patients with advanced secondary hyperparathyroidism: vitamin D receptor and cyclin-dependent kinase inhibitors, p21 and p27.". Nephrol. Dial. Transplant. 18 Suppl 3: iii9–12. PMID 12771291
- Hall M, Bates S, Peters G (1995). "Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins.". Oncogene 11 (8): 1581–8. PMID 7478582
- Motokura T, Arnold A (1993). "PRAD1/cyclin D1 proto-oncogene: genomic organization, 5' DNA sequence, and sequence of a tumor-specific rearrangement breakpoint.". Genes Chromosomes Cancer 7 (2): 89–95. doi:10.1002/gcc.2870070205. PMID 7687458
- Tao Zhang, Breslin MB, Lan MS (2009). "Zinc Finger Transcription Factor INSM1 Interrupts Cyclin D1 and CDK4 Binding and Induces Cell Cycle Arrest.". J. Biol. Chem. 284 (9): 5574–81. doi:10.1074/jbc.M808843200. PMID 19124461
- Jain S, Khuri FR, Shin DM (2004). "Prevention of head and neck cancer: current status and future prospects.". Current problems in cancer 28 (5): 265–86. doi:10.1016/j.currproblcancer.2004.05.003. PMID 15375804
External links
- American Journal of Pathology, Expression Status of p16 Protein Is Associated with Human Papillomavirus Oncogenic Potential in Cervical and Genital Lesions
- http://www.google.com/imgres?imgurl=http://www.nature.com/nrm/journal/v8/n9/images/nrm2233-f4.jpg&imgrefurl=http://www.nature.com/nrm/journal/v8/n9/fig_tab/nrm2233_F4.html&usg=__ssJ8h0vc_KBjHBdkt0I4RTEBAqk=&h=433&w=355&sz=47&hl=en&start=9&um=1&itbs=1&tbnid=md39P_1BDF-U_M:&tbnh=126&tbnw=103&prev=/images%3Fq%3Dprotein%2Bp16%26um%3D1%26hl%3Den%26tbs%3Disch:1