FACTOID # 13: New York has America's lowest percentage of residents who are veterans.
 
 Home   Encyclopedia   Statistics   States A-Z   Flags   Maps   FAQ   About 
 
WHAT'S NEW
RELATED ARTICLES
People who viewed "Telomerase" also viewed:
 

SEARCH ALL

FACTS & STATISTICS    Advanced view

Search encyclopedia, statistics and forums:

 

 

(* = Graphable)

 

 


Encyclopedia > Telomerase

Telomerase is an enzyme that adds specific DNA sequence repeats ("TTAGGG" in all vertebrates) to the 3' ("three prime") end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. The telomeres contain condensed DNA material, giving stability to the chromosomes. The enzyme is a reverse transcriptase that carries its own RNA molecule, which is used as a template when it elongates telomeres, which are shortened after each replication cycle. Telomerase was discovered by Carol W. Greider in 1984.[1] Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ... The structure of part of a DNA double helix Deoxyribonucleic acid (DNA) is a nucleic acid that contains the genetic instructions for the development and function of living organisms. ... A telomere is a region of highly repetitive DNA at the end of a chromosome that functions as a disposable buffer. ... Kingdoms Animalia - Animals Fungi Plantae - Plants Protista Alternative phylogeny Unikonta Opisthokonta Amoebozoa Bikonta Apusozoa Cabozoa Rhizaria Excavata Corticata Archaeplastida Chromalveolata Animals, plants, fungi, and protists are eukaryotes (IPA: ), organisms whose cells are organized into complex structures by internal membranes and a cytoskeleton. ... This article is about the biological chromosome. ... In biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into double-stranded DNA. Normal transcription involves the synthesis of RNA from DNA, hence reverse transcription is the reverse of this. ... Ribonucleic acid or RNA is a nucleic acid polymer consisting of nucleotide monomers that plays several important roles in the processes that translate genetic information from deoxyribonucleic acid (DNA) into protein products; RNA acts as a messenger between DNA and the protein synthesis complexes known as ribosomes, forms vital portions... The cell cycle, or cell-division cycle, is the series of events that take place in an eukaryotic cell between its formation and the moment it replicates itself. ... Carol Greider is a molecular biologist at Johns Hopkins University, who discovered the enzyme telomerase in 1984 while working with Elizabeth Blackburn. ...

Contents

Structure

The composition of human telomerase was identified in 2007 by Dr Scott Cohen and his team at the Children's Medical Research Institute in Australia. It consists of two molecules each of human Telomerase Reverse Transcriptase (TERT), Telomerase RNA (hTR or TERC) and dyskerin.[2] The two subunits of the enzyme are coded by two different genes in the genome. The coding region of the TERT gene is 3396bp, and translates to a protein of 1131 amino acids. The polypeptide folds with TERC (451 nucleotides long), which is not translated and remains as RNA. TERT has a 'mitten' structure that allows it to wrap around the chromosome to add single-stranded telomere repeats. The Childrens Medical Research Institute (CMRI) is an Australian based scientific research group created in the 1950s to perform scientific research with a commitment to better treat, and where possible, prevent childhood illness and disability so that all concerned have a better quality of life[1]. The Institute is... TERT is an acronym for TElomerase Reverse Transcriptase, a protein subgroup. ... In biology the genome of an organism is the whole hereditary information of an organism that is encoded in the DNA (or, for some viruses, RNA). ... Base pairs, of a DNA molecule. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... In chemistry, an amino acid is any molecule that contains both amino and carboxylic acid functional groups. ... A nucleotide is a chemical compound that consists of a heterocyclic base, a sugar, and one or more phosphate groups. ... Translation is the second process of protein biosynthesis (part of the overall process of gene expression). ...


TERT is a reverse transcriptase, which is a class of enzyme that creates single stranded DNA using single stranded RNA as a template. Enzymes of this class (not TERT specifically, but the ones isolated from viruses) are utilized by scientists in the molecular biological process of Reverse Transcriptase PCR (RT-PCR), which allows the creation of several DNA copies of a target sequence using RNA as a template. As stated above TERT carries its own template around, TERC. In biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into double-stranded DNA. Normal transcription involves the synthesis of RNA from DNA, hence reverse transcription is the reverse of this. ... Groups I: dsDNA viruses II: ssDNA viruses III: dsRNA viruses IV: (+)ssRNA viruses V: (-)ssRNA viruses VI: ssRNA-RT viruses VII: dsDNA-RT viruses A virus (from the Latin noun virus, meaning toxin or poison) is a microscopic particle (ranging in size from 20 - 300 nm) that can infect the... This article does not cite any references or sources. ... In molecular biology, reverse transcription polymerase chain reaction (RT-PCR) is a laboratory technique for amplifying a defined piece of a ribonucleic acid (RNA) molecule. ...


Function

By using TERC, TERT can add a six nucleotide repeating sequence, 5'-TTAGGG (in all vertebrates, the sequence differs in other organisms) to the 3' strand of chromosomes. These TTAGGG repeats, with their various protein binding partners are called telomeres. The template region of TERC is 3'-CAAUCCCAAUC-5'. This way, telomerase can bind the first few nucleotides of the template to the last telomere sequence on the chromosome, add a new telomere repeat (5'-GGTTAG-3') sequence, let go, realign the new 3'-end of telomere to the template, and repeat the process. (For an explanation on why this elongation is necessary see Telomere shortening.) A telomere is a region of highly repetitive DNA at the end of a chromosome that functions as a disposable buffer. ...


Clinical implications

Aging

The enzyme telomerase has been proposed as the key to cellular immortality, as a veritable "fountain of youth". The enzyme allows for rapid growth of cells without the problems of senescence. Embryonic stem cells, for instance, express telomerase, which allows them to divide repeatedly and form the individual. In adults, telomerase is expressed in cells that need to divide regularly, although most somatic cells do not express it. One of the main obvious symptoms of old age is decreased skin vitality, and if telomerase therapy can improve this alone, it will be an advance for those who suffer from such problems. Both Revive Skincare and TaSciences.com have telomerase-based products on the market for cosmetic purposes. Revive's Dr. Brown has claimed that it costs that company $4 million to produce a gram of telomerase. It has been suggested that Longevity genes be merged into this article or section. ... Mouse embryonic stem cells. ... The term somatic refers to the body, as distinct from some other entity, such as the mind. ...


Geron Corporation has granted a license to TAsciences.com to sell TA-65, a telomerase activator agent derived from the Chinese Astragalus plant. TA Sciences is now now selling TA-65 as a neutraceutical anti-aging product at their TA Sciences Center in New York City. [2] Geron Corporation is a biotechnology company founded by Dr. Michael West that is based in Menalo Park, California. ... Species See text. ...


A variety of premature aging syndromes are associated with short telomeres [3]. These include Werner syndrome, Ataxia telangiectasia, Bloom syndrome, Fanconi anemia, Nijmegen breakage syndrome and ataxia telangiectasia-like disorder. The genes which have been mutated in these diseases all have roles in the repair of DNA damage, and their precise roles in maintaining telomere length are an active area of investigation. While it is currently unknown to what extent telomere erosion contributes to the normal aging process, maintenance of DNA in general, and telomeric DNA specifically, have emerged as major players. Dr. Michael Fossel has suggested in an interview that telomerase therapies may be used not only to combat cancer, but to actually get around human aging and extend lifespan significantly. He believes human trials of telomerase-based therapies for extending lifespan will occur within the next 10 years. This timeline is significant because it coincides with the retirement of Baby Boomers in the United States and Europe. Werner syndrome is a very rare, autosomal recessive disorder; its most recognizable characteristic is premature aging. ... Ataxia-telangiectasia (AT) (Boder-Sedgwick syndrome or Louis-Bar syndrome) is a primary immunodeficiency disorder that occurs in an estimated incidence of 1 in 40,000 to 1 in 300,000 births (Lederman, 2000). ... Bloom syndrome is a rare inherited disorder characterized by a high frequency of breaks and rearrangements in an affected persons chromosomes, discovered and first described by dermatologist Dr. David Bloom in 1954. ... Fanconi anemia (FA) is a genetic disease that affects children and adults from all ethnic backgrounds. ... Nijmegen breakage syndrome (NBS) is a rare syndrome characterised by chromosomal instability, probably as a result of a defect in the Double Holliday Junction DNA repair mechanism. ... DNA damage resulting in multiple broken chromosomes DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. ... This article or section does not cite its references or sources. ... Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis (where cancer cells are transported through the bloodstream or lymphatic system). ... A baby boom is defined as a period of increased birth rates relative to surrounding generations. ... World map showing the location of Europe. ...


Cancer

When cells are approaching the Hayflick limit in cell cultures, the time to senescence can be extended by the inactivation of the tumor suppressor proteins - TP53 and Retinoblastoma protein (pRb). Cells which have been thus altered will eventually undergo an event termed a "crisis" when the majority of the cells in the culture die. Sometimes, a cell does not stop dividing once it reaches crisis. Typically the telomeres are lost, and the integrity of the chromosomes declines with every subsequent cell division. Exposed chromosome ends are interpreted as a double stranded breaks (DSB) in DNA; such damage is usually repaired by reattaching (religating) the broken ends together. When the cell does this due to telomere shortening, the ends of different chromosomes can be attached together. This temporarily solves the problem of lacking telomeres, but during anaphase of cell division the fused chromosomes are randomly ripped apart causing many mutations and chromosomal abnormalities. As this process continues, the cell's genome becomes unstable. Eventually, either sufficient damage will be done to the cell's chromosomes such that cell dies (via programmed cell death, apoptosis), or an additional mutation will take place that activates telomerase. The Hayflick limit was discovered by Leonard Hayflick in 1965. ... Epithelial cells in culture, stained for keratin (red) and DNA (green) Cell culture is the term applied when cells are grown in a synthetic environment. ... It has been suggested that Longevity genes be merged into this article or section. ... A tumor suppressor gene is a gene that reduces the probability that a cell in a multicellular organism will turn into a tumor cell. ... TP53 bound to a short DNA fragment. ... The Retinoblastoma protein, or pRb, is a tumor suppressor protein found to be dysfunctional in a number of types of cancer. ... Drawing of the structure of cork as it appeared under the microscope to Robert Hooke from Micrographia which is the origin of the word cell. Cells in culture, stained for keratin (red) and DNA (green). ... DNA damage resulting in multiple broken chromosomes DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. ... It has been suggested that mutant be merged into this article or section. ... A section of mouse liver showing an apoptotic cell indicated by an arrow // Apoptosis is a process of deliberate life relinquishment by a cell in a multicellular organism. ...


With the activation of telomerase, some types of cells and their offspring become immortal, that is, their chromosomes won't become unstable no matter how many cell divisions they undergo (they bypass the Hayflick limit) thus avoiding cell death as long as the conditions for their duplication are met. Many cancer cells are considered 'immortal' because telomerase activity allows them to divide virtually forever, which is why they can form tumors. A good example of cancer cells' immortality is HeLa cells, which were originally removed from the cervical cancer of Henrietta Lacks in 1951 and are still used in laboratories as a model cell line. They are indeed immortal - daily production of HeLa cells is estimated at several tons even up to this day - all from the few cells taken from Ms. Lacks' tumor. Biological immortality can be defined as the absence of a sustained increase in rate of mortality as a function of chronological age. ... The Hayflick limit was discovered by Leonard Hayflick in 1965. ... Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis (where cancer cells are transported through the bloodstream or lymphatic system). ... Tumor or tumour literally means swelling, and is sometimes still used with that meaning. ... Hela is also the German name for Hel, Poland and the cruiser SMS Hela In biological and medical research, a HeLa cell is a cell which is derived from cervical cancer cells taken from a woman named Henrietta Lacks, who died from the cancer in 1951, and circulated (without Lacks... Cervical cancer is a malignancy of the cervix. ... Henrietta Lacks (1920–1951) HeLa cells Henrietta Lacks (1920–1951) was the involuntary donor of cells from a cancerous tumor, which were cultured by George Gey to create a cell line for medical research, which is now known as the HeLa cell line. ... Year 1951 (MCMLI) was a common year starting on Monday (link will display the full calendar) of the Gregorian calendar. ... Epithelial cells in culture, stained for keratin (red) and DNA (green) Cell culture is the term applied when growing cells in a synthetic environment. ...


While this method of modeling human cancer in cell culture is effective and has been used for many years by scientists, it is also very imprecise. The exact changes which allow for the formation of the tumorigenic clones in the above experiment are not clear. Scientists have subsequently been able to address this question by the serial introduction of several mutations present in a variety of human cancers. This has led to the elucidation of several combinations of mutations which are sufficient for the formation of tumorigenic cells, in a variety of cell types. While the combination varies depending on the cell type, a common theme is that the following alterations are required: activation of TERT, loss of p53 pathway function, loss of pRb pathway function, activation of the Ras or myc proto-oncogenes, and aberration of the PP2A protein phosphatase. That is to say the cell has an activated telomerase eliminating the process of death by chromosome unstability or loss, absence of apoptosis-induction pathways and continued activation of mitosis. Cloning is the process of creating an identical copy of something. ... In molecular biology, Ras is the name of a protein, the gene that encodes it, and the family and superfamily of proteins to which it belongs. ... c-Myc is a mammalian transcription factor belonging to the bHLH (basic Helix Loop Helix)_Leucine Zipper family. ... An oncogene is a modified gene, or a set of nucleotides that codes for a protein, that increases the malignancy of a tumor cell. ... A phosphatase is an enzyme that dephosphorylates its substrate; i. ... Mitosis is the process in which a cell duplicates its chromosomes to generate two identical cells. ...


This model of cancer in cell culture accurately describes the role of telomerase in actual human tumors. Telomerase activation has been observed in ~90% of all human tumors, suggesting that the immortality conferred by telomerase plays a key role in cancer development. Of the tumors which have not activated TERT, most have found a separate pathway to maintain telomere length termed ALT (Alternative Lengthening of Telomeres). The exact mechanism behind telomere maintenance in the ALT pathway has not been elucidated, but likely involves multiple recombination events at the telomere. Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis (where cancer cells are transported through the bloodstream or lymphatic system). ...


Additional roles in cancer, heart disease, and a socioeconomic and quality of life aspect

Additional roles for telomerase Per work by Dr. Elizabeth Blackburn et al, include the upregulation of 70 genes known or suspected in cancers growth and spread through the body, and , the activation of glycolysis, which enables cancer cells to rapidly use sugar to facilitate their programmed growth rate.(roughly the growth rate of a fetus) American molecular biologist Dr. Elizabeth H. Blackburn was born in Hobart, on the island of Tasmania, Australia, on November 26, 1948. ...


E.V. Gostjeva et al (MIT) recently imaged colon cancer stem cells and compared them to fetal colon stem cells trying to make a new colon, they were the same.


Dr. Elizabeth Blackburn et al UCSF has shown work that mothers caring for their very sick children have shorter telomeres when they report that their emotional stress is at the greatest point. She also found telomerase active at the site of blockages in coronary artery tissue. This could be why heart attacks can come on so suddenly, telomerase is driving the growth of the blockage.


Other work has shown that the poor have shorter telomeres than the rich[4]. Short telomeres can lead to telomeric crisis and the initiation of cancer if many other conditions are also met, or so the discussion goes at this point.[citation needed]


Dr. Blackburn and the two other co-discoverers of telomerase won the Lasker Prize (2006) for the discovery of telomerase and subsequent work on telomerase. Dr. Blackburn also won the 2006 Gruber Genetics Prize for same. Seventy winners of the Lasker have gone on to be awarded the Nobel.


Role in other human diseases

Mutations in TERT have been implicated in predisposing patients to aplastic anemia, a disorder in which the bone marrow fails to produce blood cells, in 2005. [5]. Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. ... This article does not cite any references or sources. ...


Cri du chat Syndrome (CdCS) is a complex disorder involving the loss of the distal portion of the short arm of chromosome 5. TERT is located in the deleted region, and loss of one copy of TERT has been suggested as a cause or contributing factor of this disease. [6] 5p- karyotype Cri du chat syndrome, also called deletion 5p syndrome, or 5p minus, is a rare genetic disorder due to a missing portion of chromosome 5. ...


Dyskeratosis congenita (DC) is a disease of the bone marrow which can be caused by a mutation in the telomerase RNA subunit, TERC. Mutation of TERC only accounts for 5% of all cases, and when DC occurs by this mutation, it is inherited as an autosomal dominant disorder. Mutations in the gene Dyskerin (DKC1) account for about 35% of DC cases, and in this case the inheritance pattern is X-linked recessive. Dyskeratosis congenita (DKC) is a rare progressive bone marrow failure syndrome characterized by cutaneous pigmentation, dystrophy of the nails, leukoplakia of the oral mucosa, continuous lacrimation due to atresia of the lacrimal ducts, often thrombocytopenia, anemia and in most cases testicular atrophy. ... This article does not cite any references or sources. ...


Patients with DC have severe bone marrow failure manifesting as abnormal skin pigmentation, leucoplakia (a white thickening of the oral mucosa), and nail dystophy, as well as a variety of other symptoms. Individuals with either TERC or DKC1 mutations have shorter telomeres and defective telomerase activity in vitro than other individuals of the same age. [7] Historical data for native populations collected by R. Biasutti prior to 1940. ... Leukoplakia is a condition of the mouth that involves the formation of white leathery spots on the mucous membranes of the tongue and inside of the mouth. ...


There has also been one family in which autosomal dominant DC has been linked to a heterozygous mutation in TERT.[8] These patients also exhibited an increased rate of telomere shortening, and gentic anticipation (i.e. the DC phenotype worsened with each generation).


Telomerase as a potential drug target

Cancer is a very difficult disease to fight because the immune system cannot recognize it, and cancer cells are immortal; they will always continue dividing. Because telomerase is necessary for the immortality of so many cancer types, it is thought to be a potential drug target. If a drug can be used to turn off telomerase in cancer cells, the above process of telomere shortening will resume—telomere length will be lost as the cells continue to divide, mutations will occur and cell stability will decrease. Experimental drug therapies targeting active telomerase have been tested in mouse models, and some have now entered early clinical trials. Geron Corporation is currently conducting three human clinical trials involving telomerase inhibition using two different approaches. One is a vaccine (GRNVAC1) and the other is a lipidated drug (GRN163L). Indeed, telomerase suppression in many types of cancer cells grown in culture has led to the massive death of the cell population. However, a variety of caveats, including the presence of the ALT pathway [9], complicate such therapies. Some have reported ALT methods of telomere maintenance and storage of DNA in cancer stem cells, however Geron claims to have killed cancer stem cells with their telomerase inhibitor GRN163L at Johns Hopkins. GRN163L binds directly to the RNA template of telomerase. Even a mutation of the RNA template of telomerase would render the telomerase unable to extend telomeres, and therefore not be able to grant replicative immortality to cancer, not allow glycolysis to be inititated, and not upregulate Blackburn's 70 cancer genes. (Blackburn et al) Since Blackburn has shown that most of the bad effects of telomerase are dependent on an intact RNA template, it seems a very worthwhile target. If indeed some cancer stem cells use an alternative method of telomere maintenance, it should be noted that they are still killed when the RNA template of telomerase is blocked. According to Blackburn's opinion at most of her lectures, it is a big mistake to think that telomerase is only involved with extending telomeres. Stopping glycolysis in cancer stem cells and preventing the upregulation of 70 bad genes is probably what is killing cancer stem cells if they are using ALT methods. For other meanings, see Drug (disambiguation). ... Geron Corporation is a biotechnology company founded by Dr. Michael West that is based in Menalo Park, California. ... A telomere is a region of highly repetitive DNA at the end of a chromosome that functions as a disposable buffer. ...


References

  1. ^ Greider, C.W. & Blackburn, E.H. (1985) "Identification of a specific telomere terminal transferase activity in Tetrahymena extracts." Cell v.43, (2 Pt. 1) pp. 405-413.
  2. ^ Cohen S, Graham M, Lovrecz G, Bache N, Robinson P, Reddel R (2007). "Protein composition of catalytically active human telomerase from immortal cells". Science 315 (5820): 1850-3. PMID 17395830. 
  3. ^ Blasco MA. Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet. 2005 Aug;6(8):611-22. PMID 16136653
  4. ^ [1]
  5. ^ Image:Free_text.png Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, Lansdorp PM, Young NS. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med. 2005 Apr 7;352(14):1413-24. PMID 15814878 Free text after registration
  6. ^ Image:Free_text.png Zhang A, Zheng C, Hou M, Lindvall C, Li KJ, Erlandsson F, Bjorkholm M, Gruber A, Blennow E, Xu D.Deletion of the telomerase reverse transcriptase gene and haploinsufficiency of telomere maintenance in Cri du chat syndrome. Am J Hum Genet. 2003 Apr;72(4):940-8. Epub 2003 Mar 10. PMID 12629597
  7. ^ Marrone A, Walne A, Dokal I. Dyskeratosis congenita: telomerase, telomeres and anticipation. Curr Opin Genet Dev. 2005 Jun;15(3):249-57. PMID 15917199
  8. ^ Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A, Griffin CA, Eshleman JR, Cohen AR, Chakravarti A, Hamosh A, Greider CW. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15960-4. PMID 16247010
  9. ^ Image:Free_text.png Bryan TM, Englezou A, Gupta J, Bacchetti S, Reddel RR. Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J. 1995 Sep 1;14(17):4240-8. PMID 7556065

s. Image File history File links Free_text. ... Image File history File links Free_text. ... Image File history File links Free_text. ...


This model of cancer in cell culture accurately describes the role of telomerase in actual human tumors. Telomerase activation has been observed in ~90% of all human tumors, suggesting that the immortality conferred by telomerase plays a key role in cancer development. Of the tumors which have not activated TERT, most have found a separate pathway to maintain telomere length termed ALT (Alternative Lengthening of Telomeres). The exact mechanism behind telomere maintenance in the ALT pathway has not been elucidated, but likely involves multiple recombination events at the telomere.#REDIRECT Insert text Category: ...


See also

DNA repair DNA damage resulting in multiple broken chromosomes DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. ...


External links


  Results from FactBites:
 
Telomerase - Wikipedia, the free encyclopedia (1463 words)
Telomerase is an enzyme, that adds specific DNA sequence repeats, ("TTAGGG" in all vertebrates) to the 3' ("three prime") end of DNA strands, in the telomere regions at the ends of chromosomes which contain condensed DNA material during replication.
Telomerase activation has been observed in ~90% of all human tumors, suggesting that the immortality conferred by telomerase is required for cancer development.
Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia.
  More results at FactBites »

 
 

COMMENTARY     


Share your thoughts, questions and commentary here
Your name
Your comments

Want to know more?
Search encyclopedia, statistics and forums:

 


Press Releases |  Feeds | Contact
The Wikipedia article included on this page is licensed under the GFDL.
Images may be subject to relevant owners' copyright.
All other elements are (c) copyright NationMaster.com 2003-5. All Rights Reserved.
Usage implies agreement with terms, 1022, m